Structural Biochemistry/Volume 10

Structural Biochemistry General Terms

• INTERACTOME: The complete set of molecular interactions in cells. Molecular interactions can occur between molecules of different groups (proteins, lipids, carbohydrates, etc.) or within the same group.
• PROTEOME: The proteome is the complete set of proteins, which encompasses the functional information present in a cell or organism including the function, type and interactions of the proteins.
• GENOME: The genome is the complete set of an organism’s genetic or hereditary information.
• METABOLOME: The metabolome is the complete set of metabolites in a cell or organism that give insight into the metabolic processes.
• CATABOLISM: Catabolism represents the processes that release of energy by breaking down molecules into smaller units.
• ANABOLISM: Anabolism represents the processes that require energy for building molecules from smaller units.
• METABOLISM: Metabolism is the complete set of processes that maintain life and are divided into catabolism and anabolism.
• ENZYME ACTIVITY: Enzymatic Activity represents the ability of an enzyme to promote a particular chemical reaction or function.
• SPECIFIC ACTIVITY: Specific Activity represents the ratio of enzyme activity to the amount of protein in a mixture.
• BOND DISSOCIATION ENERGY: The bond dissociation energy is the energy required to break a bond for example the energy it takes to break a hydrogen bond is approximately 23kJ/mol.
• FLICKERING CLUSTERS: Flickering clusters are short-lived groups of water molecules that are interlinked by hydrogen bonds in liquid water. These clusters are representative of the fact that Hydrogen Bonds are easily broken and reformed.
• MICELLES: Micelles represent the non-polar regions that cluster together to present the smallest hydrophobic area to the aqueous solvent. This will remove some of the ordered-ness of water, which is favored due to the increased entropy of water.
• ISOTONIC: Isotonic means that the cells osmolarity is equal to its surroundings
• HYPERTONIC: Hypertonic means that the osmolarity of the surroundings is higher than the cell’s osmolarity causing the cell to shrink.
• HYPOTONIC: Hypotonic means that the osmolarity of the surroundings is lower than the cell’s osmolarity causing the cell to swell.
• ACIDOSIS: Acidosis is a condition where the pH of a person’s blood is below the normal blood pH of approximately 7.4.
• ALKALOSIS: Alkalosis is a condition where the pH of a person’s blood is above the normal blood pH of approximately 7.4.
• CONDENSATION REACTION: A condensation reaction involves the removal or elimination of water. (For example: ADP + P ⇒ ATP + H2O).
• HYDROLYSIS REACTION: A hydrolysis reaction involves the addition of water. (For example: the depolymerization of proteins carbohydrates and nucleic acids requires water).
• EUKARYOTES: Eukaryotes have a nuclear envelope that has a double membrane where the nuclear material is enclosed. This term literally means true nucleus.
• PROKARYOTES: Prokaryotes lack a nuclear envelope, which is typical of Archaea and Bacteria kingdoms. This term literally means before nucleus.
• BACTERIA: Bacteria are single celled microorganisms that tend to inhabit soils and surface water.
• ARCHAEA: Archaea is a kingdom of single celled microorganisms that inhabit extreme environments and more closely resemble eukaryotes.
• PHOTOTROPHS: Phototrophs derive their energy from sunlight.
• AUTOTROPHS: Autotrophs derive their energy from sunlight and their source of carbon is from CO2 (for example: vascular plants).
• HETEROTROPHS: Heterotrophs derive their energy from sunlight and their source of carbon are organic compounds (for example: green bacteria).
• CHEMOTROPHS: Chemotrophs derive their energy from oxidation of chemical fuels meaning they take reduced fuel and oxidize it by usually adding oxygen.
• LITHOTROPHS: Lithotrophs derive their energy from oxidation of inorganic fuels (for example: sulfur bacteria).
• ORGANOTROPHS: Organotrophs derive their energy from oxidation of organic fuels (for example: people).
• AEROBIC: An aerobic environment has a plentiful supply of oxygen allowing for the derivation of energy from the transfer of electrons from fuel molecules to oxygen.
• ANAEROBIC: An anaerobic environment is virtually devoid of oxygen meaning organisms obtain energy by transferring electrons to sulfate or nitrate instead of oxygen (forming H2S and N2 respectively).
• OBLIGATE ANAEROBES: Obligate anaerobes die when they are exposed to oxygen.
• FACULLATIVE ANAEROBES: Facullative anaerobes are able to live with or without oxygen.
• ENDOMEMBRANE SYSTEM: The endomembrane system is characteristic of eukaryotes and segregates specific metabolic processes thereby providing specific surfaces on which certain enzyme-catalyzed reactions can occur.

Enthalpy (delta H) - heat at constant pressure

Endothermic(pos. delta H) - heat is added to the system

Exothermic(neg. delta H) - heat is released from the system

Zeroth Law of Thermodynamics - states that two objects in contact with each other will have the same temperature Ex. A thermometer.

Spontaneous change - process that has a tendency to occur without an external influence

Entropy (S) - the measure of ‘disorder’ [Natural process is for system to become less ‘ordered’, or ‘random.’]; to become disordered

Microstate - all the quantized states of the whole system of molecules (number of microstates [W] can go up to 10^10^23)

Second Law of Thermodynamics - states that the entropy of an isolated system increases during the course of any spontaneous change

Thermal disorder - increase heat into which entropy can increase

Positional disorder - increase area into which disorder can occur

Third Law of Thermodynamics - states that a perfect crystal has zero entropy at a temperature of absolute zero: S(sub sys) = 0 at 0 K.

Extensive property - one that depends on the amount of substance Ex. entropy

Standard entropy of reaction - the entropy change that occurs when all reactants and products are in their standard states

Effects on Rate: Magnitude of k

Solvent Effects: Protic solvent: O-H or N-H’s in it v. Aprotic solvent: doesn't - solvate cations but not anions very well Polar v. Nonpolar solvent; acid/base presence can be cruical

Homogeneity Effects: homogeneous(solution) v. heterogeneous(two or more phase); surface area; particle size

Catalyst Effects: catalysts speed reactions up without being used up in the reaction; lower activation energy

Temperature Effects: (most affecting effect) there is a 2 to 4 fold increase in rate for every 10 degree increase in T

Collision Theory: 1)for a reaction to occur, ve- of reacting species must be within bonding distance, so inc. concentrations of reacting species will inc. rates 2) collisions must have correct orientation 3)collisions must have correct energy

Degenerate process - is when molecules collide but nothing is generated

Transition State/Activated Complex Theory - there is a point in a reaction at which the reactants are in transition to products (and vice versa)

References

Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007.

Structural Biochemistry Protein Terms

• PRIMARY STRUCTURE: The primary structure of a protein is the sequence of amino acids in the polypeptide. These amino acids are covalently bonded through peptide bonds.
• SECONDARY STRUCTURE: The secondary structure of a protein regards the folding of the chain of amino acids into organized sub-structures like an alpha helix, beta pleated sheet, beta turn, or omega loop. This organizational scheme is held together primarily by hydrogen bonds.
• TERTIARY STRUCTURE: The tertiary structure of a protein involves the three dimensional arrangement of a single polypeptide chain, which includes hydrophobic and hydrophilic interactions, disulfide and hydrogen bonds (non-covalent bonds), salt bridges, and motifs.
• QUATERNARY STRUCTURE: The quaternary structure of a protein is the general arrangement and assembly of several polypeptide chains into subunits. When multiple subunits are stabilized by non-covalent interactions the resulting complex is called a multimer.
• ALIPHATIC: A hydrocarbon chain that is not aromatic.
• PEPTIDE BOND / AMIDE BOND: Involves a condensation reaction that joins two amino acids and requires the input of free energy, but while the bond is thermodynamically unstable it is kinetically favorable as the rate of hydrolysis is quite slow. This bond also has considerable double bond character making amino acids relatively planar.
• DISULFIDE BONDS: These bonds are formed from the oxidation of a pair of cysteine amino acid residues thereby forming cystine and are generally involved in tertiary structure arrangements.
• PROTEIN: A protein is a linear polymer of monomer units called amino acids linked by peptide bonds. Proteins spontaneously fold into a native 3D conformation, have a wide range of functional groups, and are chemically reactive.
• PHI: Phi is the torsion angle that occurs about the rotation of the single bond from nitrogen to the alpha carbon, which allows the protein to rotate to various orientations. Clockwise is considered positive rotation by convention.
• PHOSPHODIESTER BOND: Covalent bond involving a phosphate group and two ester groups. E.g. Bond joining two nucleotides.
• PSI: Psi is the angle of rotation about the single bond between the alpha carbon and the carbonyl group. A clockwise rotation is considered positive by convention and allows proteins to fold into many conformations.
• TORSION ANGLE / DIHEDRAL ANGLE: A torsion angle is the measure of the rotation about a bond between positive and negative 180 degrees. For proteins those angles are called phi and psi and are most easily seen on a Ramachandran Diagram.
• RESIDUE: A residue is an amino acid unit in a polypeptide
• RAMACHANDRAN DIAGRAM: A Ramachandran Diagram is a visual representation of the many compilations of the torsion angles that are allowed and are forbidden in a protein’s configuration due to steric collisions.
• STERIC EXCLUSION: Steric exclusion is the fact that two atoms cannot be in the same place at the same time. This is a powerful organizing principle for protein structure.
• DOMAINS: Domains are globular units of polypeptide chains that fold into two or more compact regions and are typically connected by a flexible segment of polypeptide chain. They are usually considered part of the tertiary structure.
• MOTIFS: A motif is part of the supersecondary structure and describes unique sequences of secondary structure elements present in proteins such as helix-turn-helix or beta ribbon.
• HOMOLOGY – Having a common evolutionary origin. Sometimes used mistakenly to describe similarities between proteins or nucleic acid sequences.
• HOT SPOTS – Essential amino acid deposits of protein-binding sites that have a particularly high binding free energy. Can cluster to form densely packed ‘hot regions’.
• ACTIVE CENTRE – Protein segment that plays a key part in the catalytic reaction of the enzyme function shown by the respective protein.
• BINDING SITE – Amino acid side chains located at the binding interface.
• CENTRAL RESIDUES – Contain catalytic residues (active centres) in addition to binding sites and hit spots.

References

Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007.

Contentious Terms

These are scientific terms that currently seems to be in dispute. Whether the meaning or the usage of the terms is controversial, these terms should be used with careful considerations.

Homology

Definition

"The most fundamental relationship between two entities is homology; two molecules are said to be homogous if they have been derived from a common ancestor." Homology are further divided into two classes: Paralogs and Orthologs. Simply, homology means to have common evolutionary origin.

Controversy

The term, “homology” has been famous for being misused in the scientific communities including the scientific journals and letters. The battle to amend this misused word has a long history. Recently however, the scientific community have once again brought into a discussion for the outbreak of this misusage. 1987 was the pinnacle of this dispute with many prominent journals and scientist argued that the term homology was being misused as a concept of quantity and not quality. The term is defined as having a common evolutionary origin, but it is widely misused to explain the comparison of proteins.

A research was done recently to confirm the accuracy of the term usage after the heated argument 20 years ago. Through reviewing hundreds of Pubmed documentations published in 2007, every article with the term homology was read and verified. However, only 57% of the 1966 reviewed had used the term homology correctly. There is still a misleading idea that homology can be used quantitatively. Also, interestingly, the error in the terminology was significantly lower in articles with language other than English. This study ultimately shows that the debate from 1987 still hasn't been fully acknowledged or applied.

Structural Biochemistry Carbohydrate Terms

• MONOSACCHARIDE: Monosaccharides are the simplest carbohydrates and are either ketoses or aldoses that have two or more hydroxyl groups. Monosaccharides typically have the empirical formula (C-H2O)n, which is a carbon hydrate, and are important fuel molecules as well as building blocks of nucleic acids.
• KETOSE: Ketoses are carbohydrates that contain a keto group or simply a ketone like dihydroxyacetone.
• ALDOSE: Aldoses are carbohydrates that contain an aldehyde group like glyceraldehyde.
• ENANTIOMER: Enantiomers are mirror images of one another. Every chiral center on a molecule must have the opposite configuration. Enantiomeric carbohydrates have either the D or L form.
• DIASTERIOMER: Diasteriomers are molecules that have opposite configurations at one or more of the chiral centers but at least one chiral center must remain the same. Therefore diastereomers are not mirror images of one another.
• EPIMER: An epimer is a sugar that differs in configuration at a single asymmetric center. For example D-glucose and D-mannose are epimeric at C-2.
• HEMIACETAL: Hemiacetals form when an aldehyde reacts with an alcohol. Carbohydrates with an aldehyde group or aldoses in open-chain forms will cyclize into rings by forming a hemiacetal.
• HEMIKETAL: Hemiketals form when a ketone reacts with an alcohol. Carbohydrates with a keto group or ketoses in open-chain forms will cyclize into rings by forming a hemiketal.
• ANOMER: The C-1 carbon atom is called the anomeric carbon atom. The alpha and beta forms are called anomers. The alpha designation means that the hydroxyl group attached to C-1 is on the opposite side of the ring from the CH2OH at the carbon atom that determines whether the sugar is designated D or L. The beta designation means that the hydroxyl group is on the same side as the CH2OH at the chiral center.
• GLYCOSIDIC BOND: Glycosidic bonds can join one monosaccharide to another. These bonds are formed by the reaction of a hemiacetal or a hemiketal with an alcohol to form a acetal or a ketal respectively with the loss of water. So the formation of a glycosidic bond is a dehydration reaction.
• REDUCING SUGAR: A reducing sugar can act as a reducing agent and is any sugar the in solution has an aldehyde or a ketone group; like for example Maltose.
• NONREDUCING SUGAR: A nonreducing sugar cannot act as a reducing agent and is any sugar the in solution will not convert to an aldehyde or a ketone group; like for example Sucrose.
• GLYCOPROTEIN: A carbohydrate group can be covalently attached to a protein to form a glycoprotein. Glycoproteins are components of cell membranes. Carbohydrates are linked to proteins through Asparagine in an N-linkage or through Serine or Threonine in an O-linkage. Glycosylation sites can be detected within amino acid sequences.
• PYRANOSE: A pyranose is a carbohydrate that has a five-carbon and oxygen ring in its chemical structure.
• FURANOSE FORM: A pyranose is a carbohydrate that has a furan ring structure with four carbons and an oxygen atom.
• CONFORMATIONAL ISOMERS: Molecules that differ from each other only by rotation across a single bond.
• HOMOPOLYSACCHARIDE: A carbohydrate chain that consists of only one kind of carbohydrate monomer.
• HETEROPOLYSACCHARIDE: A carbohydrate made of more than one type of monomer.
• GLYCOSYLATION: This is the process by which carbohydrates are added to proteins or lipids, or other molecules as well.
• LECTINS: Promote interactions between cells.
• OLIGOSACCHARIDE: It is a carbohydrate chain that consists of three to ten residues.

References

Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007.

Structural Biochemistry Lipids and Cell Membrane Terms And Information

• FATTY ACID: Fatty acids are long hydrocarbon chains of various lengths and degrees of unsaturation with carboxylic acid groups. The fatty acid names are based on the parent hydrocarbon chain. Fatty acids are the key constituents of lipid and lipid owe their hydrophobic properties to them.
• PHOSPHOLIPID: Phospholipids are abundant in all biological membranes and are made up of one or more fatty acids, a platform to which the fatty acids are attached, a phosphate, and an alcohol group. The alcohol group can vary adding additional diversity.
• SPHINGOSINE: Is a more complex alcohol that can be used as a platform in phospholipids. This alcohol is an amino alcohol with a long unsaturated hydrocarbon chain. The amino group here links to the fatty acid through an amide bond.
• PHOSPHOGLYCERIDE: The most common platform for a phospholipid is glycerol. Phosopholipids with glycerol platforms are called phosphoglyceride. These molecules also have two attached fatty acid chains connected with esterified bonds and a phosphate group also connected to the glycerol in an esterified bond.
• GLYCOLIPID: Glycolipids are sugar-containing lipids and are derived from sphingosine. Here the fatty acid is acylated to the amino group and a sugar unit is linked to the primary hydroxyl group.
• CHOLESTEROL: Cholesterol is a lipid with a steroid basis, a hydroxyl group on one end, and a hydrocarbon tail at the other end. Cholesterol is parallel to the fatty acid chains of phospholipids with the hydroxyl group interacting with the polar head groups of the phospholipids.
• AMPHIPHATIC: Amphiphatic molecules contain both a hydrophilic and a hydrophobic part like for example a membrane lipid, which has its hydrophobic fatty acid chains parallel to one another while the hydrophilic head group interacts with the polar media.
• LIPID BILAYER: Lipid bilayers are highly impermeable to ions and polar molecules. Lipid bilayers form from a thin membrane of two layers of lipid molecules, which make a flat, continuous, extensive, self-sealing barrier.
• LIPOSOME: A liposome is also known as a lipid vesicle and has a small aqueous compartment surrounded by a lipid bilayer. This can be used to trap molecules inside and test the permeability of a membrane.
• INTEGRAL MEMBRANE PROTEIN: Integral membrane proteins heavily interact with the hydrocarbon chains of membrane lipids and are released by agents that will fight for the nonpolar interactions.
• PERIPHERAL MEMBRANE PROTEIN: Peripheral membrane proteins are bound to the membrane through electrostatic and hydrogen bond interactions that occur with the polar head groups of the membrane lipids.
• LATERAL DIFFUSION: Lateral diffusion is the constant lateral movement (from side to side) that the lipids undergo in the membrane. This can be proven through photo-bleaching and indicates that the lipid bilayer is an asymmetric fluid structure.
• TRANSVERSE DIFFUSION: Transverse diffusion is when the lipid will flip-flop across the membrane and occurs far less frequently that lateral diffusion.
• MICELLE: It is an aggregate of fatty acid molecules with the hydrophobic tails pointing inward, and the hydrophilic heads pointing outward.
• HYDROPATHY INDEX: Each amino acid residue is given a certain number that represents the extent of the hydrophobic nature of the protein. More hydrophobic amino acids have higher values.

Common Features which underlie the diversity of Biological Membranes

Membrane are diverse in structures and functions. Some important attributes include:

• Have sheetlike structure, two molecules thick which form closed boundaries between different compartment. Thickness of membrane from 60 A (6nm) – 100 A (10nm)
• Consist mainly of lipids / proteins. Mass ratio of lipids to proteins ranges from 1:4 to 4:1.
• Consist of carbohydrates which link to lipids and proteins
• Membrane lipid small molecule which have BOTH hydrophilic and hydrophobic moieties. Lipids form closed bimolecular sheets in aqueous media (lipid bilayers) and are barriers to flow of polar molecules
• Specific protein mediate distinctive function of membranes. Serve as pump, channels, receptors, energy transducer, and enzymes.
• Noncovalent assemblies meaning constituent protein and lipid molecules are held together by noncovalent interactions
• Asymmetric, two faces always differ from one another
• Fluid structures. Lipid molecules diffuse rapidly in plane of membrane along with proteins unless held down by specific interactions. Can be regarded as two-dimensional solutions of oritented protein / lipid
• Most cell membrane electronically polarized. Inside is negative (approximately 60mV). Membrane potential play key role in transport, energy conversion, and excitability

Fatty Acid Key Constituent of Lipids

Fatty acid: long hydrocarbon chains of different length/degree of unsaturation which are terminated with carboxylic acid groups. Name is derived from parent hydrocarbon by substitution of oic for final e.

• EX. C₁₈ saturated fatty acid = octadecanoic acid
• EX. C₁₈ with one double bond = octadecenoic acid
• EX. C₁₈ with two double bond = octadecadienoic acid
• EX. C₁₈ with three double bond = octadecatrienoic acid

How to Name Fatty Acids

• Carbon 2 and 3 referred to as Alpha () and Beta ()
• Methyl carbon at end of chain is called omega ()-carbon atom
• Position of double bond represented by triangle/delta ()followed by superscript number

- EX. cis-9 = cis double bond between carbon 9 and 10

• Position of double bond can be denoted by counting distance from distal end, with omega ()-carbon atom (methyl carbon) as C-1.
• Fatty acids are ionized at physiological pH, refer to them in carboxylate form

Fatty acids vary in chain length and degree of unsaturation (Facts about fatty acids)

• Fatty acid usually contain even number of carbon atoms (between 14-24).
• 16-18 carbon chain fatty acids are most common.
• Configuration of most double bond unsaturated fatty acid is cis
• Alkyl chain may be saturated and can contain one or more double bond
• Unsaturated fatty acid have lower melting point than saturated fatty acids of same length
• Chain length affects melting point , short chain length and unsaturation enhance fluidity of fatty acids and their derivatives

Three major kinds of Membrane Lipids

Phospholipid (major class) - Constructed of four components, one or more fatty acids, platform to which fatty acids are attached, a phosphate, and alcohol attached to phosphate - Provide hydrophobic barrier, whereas remainder of molecule is hydrophilic which aid to enable interaction with aqueous environment

Glycolipid, super-containing lipids - Simplest glycolipid is called cerebroside, which contains single sugar residue (glucose or galactose)

Cholesterol, steroid built from four linked hydrocarbon rings

Phospholipid and Glyccolipid readily form bimolecular sheets in aqueous media

Membrane formation is a consequence of amphipathic nature of molecules. It helps enable phospholipid to form membrane due to polar head groups favoring contact with water while hydrocarbon tails interact with one another.

• Molecules can use a micelle to arrange themselves [pic of micelle]
• Micelle: process in which polar head groups form the outside surface which is surrounded by water while hydrocarbon tails are inside, interacting with one another

• Favored structure for phosopholipids and gylcolipids are a biomolecular sheet due to two fatty acid chains of phosopholipid/glycolipid are too bulky to fit interior of micelle.
• Size of micelle (less than 200A (20nm) versus size of bimolecular sheet (107 A (106 nm)

• Lipid bilayer form spontaneously by self-assembly process (structure of bimolecular sheet is inherent in structure of constituent lipid molecules)

References

Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007.

Biochemistry Berg 7th Edition

Structural Biochemistry DNA and RNA Terms

• NUCLEOSIDE: A nucleoside consists of a sugar and one of the four bases (ATCG) present in DNA
• NUCLEOTIDE: A nucleotide consists of a sugar, one of the four bases (ATCG) present in DNA, and a phosphate, meaning a nucleotide is a nucleoside plus a phosphate.
• SEMI-CONSERVATIVE REPLICATION: The separation of the double helix creates two single-stranded templates onto which new double helices can be made. Therefore in semi-conservative replication the newly made DNA strand is half parental and half constructed.
• TRANSLATION: Translation is the process of protein synthesis. Here messenger RNA or mRNA that originated from transcription is read and interpreted in the ribosome to produce a specific amino acid chain thereby forming a protein.
• TRANSCRIPTION: Transcription is the process of creating an mRNA strand or quite simple an RNA copy of DNA where the base pairs are (AUGC) and RNA polymerase is used to catalyze the formation of the nucleic acid based polymer. The primary transcript of RNA will undergo various alterations like the addition of a Cap, a Poly(A) tail, and splicing to remove introns.
• TRANSFER RNA: Transfer RNA will transfer a specific amino acid to the ribosomal site of protein synthesis during translation. Here an anticodon on the tRNA will match a codon on the mature mRNA strand, which will correspond to a singe particular amino acid.
• MICRO RNA: Micro RNA or miRNA binds to complementary sequences of mRNA and thereby silence or inhibit the translation of that mRNA transcript into a protein.
• MESSENGER RNA: Messenger RNA or mRNA is a molecule that carries the blueprint for the building of a protein. The mRNA strand comes from a copy of DNA and carries with it the coding information for protein synthesis.
• RIBOSOMAL RNA: Ribosomal RNA or rRNA is the major component of RNA that gives the ribosome its ability catalyze the synthesis of amino acids into fully functional proteins.
• SMALL INTERFERING RNA: Small interfering RNA or siRNA is also known as short interfering RNA or silencing RNA because it is involved in RNA interference, which stops the expression of RNA into a protein.
• snRNA: These are small RNA molecules found in eukaryotic cells that are involved in RNA splicing
• SIGNAL RECOGNITION PARTICLE: It is a ribonucleoprotein which recognizes specific proteins and targets them to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes
• TELOMERASE RNA: RNA is present in the form of a number of repeats of certain nucleotides at the ends of chromosomes in order to protect the DNA from breakage
• RIBOZYME: It is an RNA molecule that has the ability to catalyze a chemical reaction due to the fact that it possesses a definite 3-D structure.
• PURINE: A purine is an aromatic heterocyclic compound. Adenine and guanine are purine ribonucleotides.
• PYRIMIDINE: It is also a class of aromatic heterocyclic compound found in DNA and RNA. Thymine and Cytosine are pyrimidines.
• INTRON: An intron is a noncoding section of RNA that will not be expressed into a protein and must be removed through splicing.
• EXON: An exon is a coding section of RNA that will be expressed into a protein and therefore must be linked together with other exon segments to make a mature RNA transcript.
• Ribose: The pentose sugar found in RNA
• Deoxyribose: The pentose sugar found in DNA
• DNA polymerase: One of the enzymes responsible for DNA replication
• ADENINE: One of the five nucleotides found in DNA and RNA
• THYMINE: One of the nucleotides found in DNA. In RNA, this base is replaced with uracil
• URACIL: One of the nucleotides found in RNA. In DNA, this base is replaced with thymine
• CYTOSINE: One of the nucleotides found in DNA and RNA
• GUANINE: One of the nucleotides found in DNA and RNA
• PCR: Polymerase Chain Reaction - a process by which a specific sequence of DNA is exponentially amplified
• Gel Electrophoresis: A technique used to send fragments of DNA across an agarose gel, separating the fragments by size.
• SOUTHERN BLOT: is a method used for detecting a specific DNA sequence in DNA samples. Southern blotting combines electrophoresis - separating DNA fragments to a filter membrane and subsequent fragment dection by probe.
• NORTHERN BLOT: technique used to detect RNA in a sample. Uses electrophoresis to separate RNA samples by size and dection with probe. Similar to southern blot.

In a DNA, cytosine will link with tyrosine by triple bonds. Guanine will link with adenine by double bond.

References

Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007.

Structural Biochemistry Evolution and Bioinformatics Terms

• HOMOLOG: Two molecules are said to homologous if they have been derived from a common ancestor. Homologous molecules or homologs are divided into two classes: paralog and ortholog. Homology is often manifested by significant similarity in nucleotide or amino acid sequence and almost always manifested in three-dimensional structure.
• PARALOG: Paralogs are homologs that are present within one species. Paralogs often differ in their detailed biochemical functions. For example, human ribonuclease, which is a digestive enzyme, and angiogenin, which stimulates blood vessel growth, are structurally very similar but functionally very different.
• ORTHOLOG: Orthologs are homologs that are present within different species and have very similar or identical functions. For example, human ribonuclease, which is a digestive enzyme and bovine ribonuclease, which is also a digestive enzyme, are both structurally similar and functionally similar but are present in different species.
• SEQUENCE ALIGNMENT: Sequence alignment is a method to examine the similarity between two amino acid sequences. This method compares all possible juxtapositions of one protein structure with another and in each case recording the number of identical residues that are aligned with one another. This comparison is made by sliding one sequence past the other sequence, one amino acid at a time, and counting the number of matched residues (different scoring methods instead of identity can be used).
• CONSERVATIVE SUBSTITUTION: A conservative substitution replaces one amino acid with another that is similar in size and chemical properties. Such conservative amino acid substitutions may have minor effects on protein structure and can thus be tolerated without compromising function. This leads to a need to find a better way to score the similarity of sequences.
• IDENTITY MATRIX: This type of matrix scores a value of 1 for every time two amino acids or DNA base pairs align, and zero at all other times. Conservation is not taken into account.
• SUBSTITUTION MATRIX: A substitution matrix is a large scoring guide to tell you how to rank the similarity of two amino acid sequences. A large positive score corresponds to a substitution that occurs frequently. A large negative score corresponds to a substitution that occurs rarely.
• DIVERGENT EVOLUTION: In divergent evolution two similar aspects of an organism or the organisms themselves arise from a common ancestor or origin.
• CONVERGENT EVOLUTION: In convergent evolution two proteins for example that evolved independently may have converged on a similar structure to perform a similar biochemical activity. The structure for example may have been an effective solution to a biochemical problem that both species faced. The process of different evolutionary pathways that lead to the same solution is convergent evolution. For example, both birds and insects have wings but they do not share a common ancestor.
• EVOLUTIONARY TREES: Evolutionary trees are descriptive pictures in the form of a branching tree to show divergence and inheritance from a common ancestor.
• COMBINATORIAL CHEMISTRY: Combinatorial chemistry is the process of producing large populations of molecules en masse and selecting between them for a particular biochemical property. First you generate a diverse population, second you select members based on a certain criterion, and third reproduce the selected members to enrich the population for even better members of the population that will fulfill the criterion even better. This method is evolution in vitro or in a laboratory, and typically utilizes PCR and affinity chromatography, which is incredibly useful for better understanding molecular evolution.

References

Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007.

Structural Biochemistry Enzyme Terms

• ENZYME: Enzymes are the catalysts of biological systems and are remarkable molecular devices that determine the patterns of chemical transformations. Nearly all known enzymes are proteins, have great catalytic power, and high specificity for the transition state. Enzymes do not change the thermodynamics of a reaction they just accelerate the reactions or adjust the kinetics.
• SUBSTRATE: Enzymes are highly specific both in the type of reaction they can catalyze and in their choice of reactants. The reactants that enzymes bind with are called substrates.
• COFACTOR: Often times the catalytic activity of an enzyme is due to the presence of small molecules called cofactors. Cofactors are divided into two groups: 1) metal ions and 2) small organic molecules like vitamins called coenzymes.
• APOENZYME: An enzyme that requires a cofactor and is currently lacking its cofactor is called an apoenzyme.
• HOLOENZYME: An enzyme that is catalytically active is called a holoenzyme if that enzyme is a complete apoenzyme plus its needed cofactor.
• COENZYME: Coenzymes are a type of cofactor and are small organic molecules like vitamins that can be either tightly or loosely bound to an enzyme. Tightly bound coenzymes are called prosthetic groups.
• PROSTHETIC GROUP: Prosthetic groups are coenzymes that are tightly bound to an enzyme.
• TRANSITION STATE: The transition state of a chemical reaction is the intermediate stage between a substrate or reactant and the product. The transition state has a higher free energy that the initial substrate stage and the final product stage.
• FREE ENERGY OF ACTIVATION: The rate of a reaction depends on the free energy of activation or delta G of the transition state, which largely unrelated to the normal delta G of a reaction. The enzyme will help to lower this free energy of activation by helping to stabilize the transition state thereby increasing the rate of the reaction and the likelihood that products will form.
• FREE ENERGY: Free energy is given the symbol G. The free energy difference or delta G is the determinate of whether a reaction will proceed spontaneously or will require an input of free energy to drive the reaction to completion. If delta G is negative the reaction is exergonic and spontaneous. If delta D is positive the reaction endergonic and will not proceed spontaneously.
• ACTIVE SITE: The active site of an enzyme is the region that binds the substrate or substrates and the cofactor if present. It also contains the residues that directly participate in the making and breaking of bonds. The residues of the active site are called the catalytic groups. The active site is typically a cleft or crevice, takes up a relatively small part of the total volume of the enzyme, have unique microenvironments, and bind to substrates with weak interactions.
• INDUCED FIT: Induced fit is where the active site on an enzyme will assume a shape that is complementary to that of the substrate only after the substrate is bound. This is a dynamic recognition and is contrary to the key and lock model of enzyme-substrate binding.
• SEQUENTIAL REACTION: In a sequential reaction all the substrates must bind to the enzyme before any product is released. Sequential reactions come in two types: 1) ordered, where the substrates bind to the enzyme in a defined sequence, and 2) random, where the order of the substrates binding and the order of the products released does not matter as long as all substrates bind before any product is released.
• KINETICS: The study of the rates of chemical reactions is called kinetics and the specific study of the rates of enzyme-catalyzed reactions is called enzyme kinetics.
• DOUBLE-DISPLACEMENT REACTION: In the double displacement reaction or ping-pong reaction, one or more of the products are released before all the substrates bind to the enzyme. The key feature in a double displacement reaction is the existence of a substituted enzyme intermediate, in which the enzyme is temporarily modified.
• ALLOSTERIC ENZYME: Allosteric enzymes consist of multiple subunits and multiple active sites and do not obey Michaelis-Menten kinetics. Allosteric enzymes instead display sigmoidal plots of reaction velocity versus substrate concentration. An example of an allosteric enzyme is hemoglobin, where the subunits act cooperatively.
• COMPETITIVE INHIBITION: Competitive inhibition is a type of reversible inhibition where an enzyme can either bind to the substrate like normal or bind to the inhibitor but cannot bind to both the substrate and the inhibitor. A competitive inhibitor diminishes the rate of catalysis by reducing the proportion of enzyme molecules bound to a substrate. This type of inhibition does not affect the rate of reaction, so the V-max does not change. However, the K-m of the reaction increases because the inhibitor is competing with the substrate for the active site. A competitive inhibitor can be overcome with an increased concentration of substrate in the system.
• UNCOMPETITIVE INHIBITION: An uncompetitive inhibitor is distinguished by the fact that the inhibitor binds only to the enzyme-substrate complex. After the inhibitor binds to the enzyme-substrate complex, it greatly lengthens the time it takes for catalysis to occur. As a result, V-max decreases. Since the inhibitor will only bind to the enzyme-substrate complex, the K-m actually decreases.
• NONCOMPETITIVE INHIBITION: A type of inhibition where the inhibitor binds to a site that is not the active site of an enzyme. After binding to the enzyme, the inhibitor causes a conformational change in the enzyme, hampering its ability to perform catalysis. Because of this, the V-max of the reaction decreases. Since the inhibitor does not affect the affinity of the enzyme for its substrate, K-m remains unchanged.
• MIXED INHIBITION: In mixed inhibition a more complex pattern of inhibition is utilized where a single inhibitor both hinders the binding of a substrate and decreases the turnover number of the enzyme.
• Lock and Key – A mechanism used to explain enzymatic activity. It states that each enzyme has a shape that matches a particular substrate and that the fit is similar to that of a lock and a key. In this mechanism, the enzyme does not change shape. This mechanism has proven to be INCORRECT.
• Michaelis-Menten – A model of enzyme kinetics that specifically describes the rates of irreversible enzymatic reactions. It only applies for the steady-state phase of reactions.
• K-m – The Michaelis constant. It is also known as the affinity constant because it describes the affinity of an enzymatic active site for its substrate. The lower the affinity constant, the greater the affinity an enzyme has for its substrate.
• Feedback inhibition – A type of inhibition in which a product of an enzymatic pathway inhibits the first enzyme of that pathway.
• Cooperative activity of active sites – A property that allows the state of one active site to affect the state of all the other active sites in an enzyme. For example, in a cooperative enzyme, the binding of substrate to one active site will make all of the other active sites more likely to bind to substrates.
• R-state – One of two states that enzymes may have. This is called the relaxed state because the active sites of the enzyme have a great affinity for their substrate.
• T-state – One of two states that enzymes may have. This is called the tense state because the active sites of the enzyme have a low affinity for their substrate.
• Isoenzymes – Isoenzymes are two enzymes that have different amino acid sequences yet perform the same function.
• Burst Phase – The burst phase of a reaction occurs near the beginning of the reaction. At this time, there is no product and a great amount of enzyme and substrate. The rate of reaction at this point is very great and Michaelis-Menten kinetics does not apply to this phase.
• Steady-State Phase – The second phase of a reaction where there is a measurable amount of product. At this point, Michaelis-Menten kinetics can be applied.
• Activation Energy- A threshold that must be crossed in order to facilitate a chemical reaction. here are three ways to reach the activation energy: by raising the temperture of the system, increasing the concentration of reactions, or by using an enzyme or catalyst.

References

Berg, Jeremy M., Tymoczko, John L., and Stryer, Lubert. Biochemistry. 6th ed. New York, N.Y.: W.H. Freeman and Company, 2007.

Overview

Apotosis is a normal process during development and removing cells. These cells can develop to be cancerous cells.

Apoptosis is the programmed death of a cell. It occurs naturally in multicellular organisms and is used to regulate dead cells. Apoptosis occurs daily in human beings destroying naturally anywhere between 20 to 70 billion cells and those cells end up being replaced by newer cells.

During Apoptosis, cells will:

• Shrink
• Develop bubble-like blebs on their surface
• Have the chromatin in their nucleus degraded
• Have their mitochondria break down with the release of cytochrome c
• Break into small, membrane-wrapped, fragments
• Release ATP and UTP
• Their nucleotides will bind to receptors on phagocytic cells and this will serve as a signal to attract dying cells
• The phospholipid phosphatidylserine will be exposed on the surface
• The exposed phospholipid will serve as a “eat me” signal, which will induce the phagocytes to engulf the cell fragments
• The phagocytic cells secret cytokines that inhibit inflammation

This orderly pattern of events is called programmed cell death, also known as apoptosis.

Apoptosis was discovered by German scientist Carl Vogt who first detailed the events of apoptosis. This discovery was then later given a more precise definition by Walther Flemming. Since the 1990s apoptosis has started to become more in the mainstream and being investigated more. It truly started in the 1960s when it was seen occurring under the microscope. The picture below is mouse liver cells and the one stained is going through apoptosis.

Since the pathway through apoptosis is very long if one biochemical reaction is not carried out it can eventually lead to cells that do not die and go on creating havoc in the organism. If the cells do not go through this natural phase in their life cycle they can end up causing diseases and/or disorders. This problem can be linked to the creation of cancer by a malfunctioning cell being able to reproduce and pass on any bad organelles or incorrect DNA sequences.

Below is a picture from the Wikimedia Commons briefly showing a depicted drawing of how the apoptosis occurs in the cell:

Apoptosis was studied in roundworms and in the final stages of its cell death, there discovery of the death-inducing protease CED-3 activation became the cause of the apoptosis. In order to regulate these proteases, CSP-3 was discovered to block CED-3 autoactivation and ultimately, to decrease signs of apoptosis during the developmental stages of roundworms. CSP-3 is a capspase homolog which only works in somatic cells. Therefore, germ cells are not affected by the CSP-3.

Necessity of apoptosis in cells

• Apoptosis is needed for the proper development and formation of body parts. For example, the formation of fingers and toes of a fetus is made possible by apoptosis of the tissue between them.
• Apoptosis is needed to destroy cells that pose threats to the well-being of the organism as a whole. For example, the destruction of cell with damaged DNA.

Required factors for cell's apoptosis to occur

• There is a withdrawal of positive signals. Cells need to receive continuous stimulation, positive signals, from other cells or they need a continuous adhesion to a surface in order to survive.

For example: The withdrawal of growth factors of neurons will cause apoptosis because the growth factors serve as positive signals and are crucial for cell development

• There is a receipt of negative signals.

For example: The increase of oxidants inside the cell or the accumulation of misfolded proteins.

The mechanism of apoptosis

There are 3 different mechanisms for cell apoptosis.

Apoptosis triggered by internal signals: the intrinsic or mitochondrial pathway

• In a healthy cell, the protein Bcl-2 is displayed on the surface of the mitochondria’s outer membrane. This protein inhibits apoptosis.
• Internal damage to the cell causes the protein, Bax, to migrate to the surface of the mitochondria and inhibits the effect of Bcl-2 and stick to the outer membrane surface of the mitochondria. Bax punches holes in the outer membrane and causes cytochrome c to spill out.
• Cytochrome c uses the energy provided by ATP and proceeds to bind to the protein Apaf-1 (“apoptotic protease activating factor-1”).
• The binding of cytochrome c to Apaf-1 forms apoptosomes.
• Apoptosomes bind to caspase-9 and activates it. Caspase-9 is a protease that cleaves proteins.
• As caspase-9 cleaves proteins, it activates other caspases from its family. Such as caspase-3 and caspase-7.
• A cascade of proteolytic activity is created by the activation of caspases. These proteolytic activities lead to the digestion of structural proteins in the cytoplasm, the degradation of chromosomal DNA, and the phagocytosis of the cell.

Apoptosis triggered by external signals: the extrinsic or death receptor pathway

• Integral membrane proteins, such as Fas and TNF receptor, have receptors that are exposed at the surface of the cell.
• Binding of the complementary death activator, such as FasL and TNF, sends a signal to the cytoplasm that leads to the activation of caspase-8.
• Caspase-8, similar to caspase-9, activates a cascade of proteolytic activities, which leads to the phagocytosis of cell.

Apoptosis-Inducing Factor (AIF)

• Neurons undergo apoptosis without the use of caspases.
• AIF is a protein that is located in the intermembrane space of the mitochondria.
• When a cell receives its death signal, AIF, which is released from the mitochondria, migrates into the nucleus and binds to the DNA, which then triggers the destruction of DNA.
• Beside programing cell death, AIF also plays a important mitochondrial role in healthy cells. "A segment of AIF which is dispensable for its apoptotic function carries an NADH-oxidase domain that regulates the respiratory chain complex I and is required for cell survival, proliferation and mitochondrial integrity."

Researched results in Mitochondrial functions of AIF

Recent researches using mutant mice have helped in understanding of mitochondrial functions of AIF. For example, AIF-deficent mice are used as a model of complex I deficiency which shows a general reprogramming of mitochondrial metabolism. In human, the deficiency of complex I causes >30% of mitochondrial diseases, and it mainly affects on infants which shows a variety of symptoms such as epileptic seizures, blindness, deafness, axaxia, cognitive deficiency, myopathy and cardiomyopathy.

Researches have shown that the uncharacterized splice isoforms of AIF whose tisue and cell type-specific expression pattern can be the cause of some tissue-specific effects in AIF deficiency. In addition, the failure in detecting AIF mutations might lead to the embryonic lethality of AIF deficiency, which observed in mutant mice.

Research have also shown than a 80% reduction in the AIF expression allows the development of Hq in mice and affects on health of adult animals due to an aggravating complex I deficiency.

Role of AIF in the survival, proliferation and metabolism of cells

Mutant mice are used in studies of role of AIF in survival, proliferation and metabolism of cells. If level of AIF presence is low, it will not affect the inheritance of Hq mutation and has no major effect in exhibit growth retardation. An reduction of AIF level over time reduces major effects on the health of aging adult mice. The complete loss of AIF would cause the incompatibility with intrauterine development, and also tend to cause AIF-null mice due to the failure of homologous recombination.

Applications

Apoptosis and Organ Transplants

• Certain body parts, such as the testes and the anterior chamber of the eye, are not susceptible to antigen invasions. It turns out that these cells produce FasL at high rates, therefore, antigens, which produce Fas, would be killed as soon as they enter these sites.
• This discovery will potentially aid transplant recipients greatly, because the transplanted organs will less likely be susceptible to the attacks of the host body’s cell-mediated immune system if artificial cells made to produce high levels of FasL can be effectively inserted into the transplanted organs.
• So far, clinical trials on animals have been conducted. Allografts synthesized to express FasL have shown increases survival rate for kidneys but not for hearts.

Apoptosis in Plants

• Plants too undergo programmed cell death. Apoptosis may aid the plant in halting the spread of a virus infection.
• The mechanism of apoptosis in plants also involves caspases, which cleaves at the Asp residue. However, the activation of caspases destroys the central vacuole, which disintegrates the rest of the cell, and not the DNA.

Reference

Influential Structural Biochemists

Pepsin

Dorothy Crowfoot Hodgkin (1910–1994) is credited with being the founder of protein crystallography. In addition to further developing and refining the technique of X-ray crystallography, she determined the three dimensional structures of pepsin, cholesterol, lactoglobulin, ferritin, tobacco mosaic virus, penicillin, vitamin B-12, and insulin, among many others. She was the first person to discover the shape of a globular protein (pepsin), and she won the 1964 Nobel Prize in Chemistry for determining the molecular shape of hundreds of molecules.

Dorothy Crowfoot graduated from Somerville College of Oxford in 1932 with a degree in chemistry. She began her doctoral work at Cambridge in 1933 with Dr. J.D. Bernal, where she first studied the structural arrangement in atoms of crystals. Realizing that she could use X-ray crystallography to study more complex molecules, she determined that proteins should be studied with the “mother” matrix surrounding them and not air dried, as was standard procedure at the time.

Cholesterol

Further improvements she devised for the technique of X-ray crystallography occurred during her study of cholesterol iodide and over one hundred other steroids. Her accomplishments include the reporting of unit-cell dimensions, recording of reactive indices with respect to their crystallographic axes, which showed the molecules crystal packing, and the elucidation of the hydrogen-bond scheme among atoms. These techniques were a major breakthrough for legitimizing X-ray crystallography as an accurate analytical technique because her analyses were the first that were based on three dimensional calculations and that established the stereochemistry at each carbon atom.

Penicillin core

In 1934 she returned to Oxford on a research fellowship, where she crystallized and X-ray photographed insulin. To determine its structure, she worked with an isomorphous crystal, a derivative molecule where a single atom is replaced by a heavier one. Thirty four years later, she would finally find success in determining the structure of insulin. Meanwhile, she received her doctorate from Cambridge University and married Thomas Hodgkin in 1937 and began her work on determining the structure of penicillin. She determined that there were three derivatives of benzylpenicillin, sodium, potassium, and rubidium. She used the techniques of isomorphous replacement, optical analogs, and difference maps to elucidate the structure. She also used the first IBM analog computers to do the X-ray calculations, which was the first use of an electronic computer to solve a biochemical problem. Penicillin was instrumental in treating wounded soldiers during World War II, and saved many lives. Knowing penicillin's structure enabled the synthesis of chemically modified penicillin, crucial for the high demand encountered during the war. While completing her penicillin research, Dr. Hodgkin was named a fellow of the Royal Society, Britain's premiere scientific organization, in 1947.

VitaminB12

From 1955 to 1961 she worked on determining the structure of vitamin B-12 by locating the positions of the heavy atoms, using direct Patterson methods, and then calculating the three-dimensional Fourier series using observed F values and phases based only on the heavy atom's positions. By pioneering the use of Patterson maps, Dorothy was able to approximate the correct electron density series.

In addition to receiving the Royal Medal, she also won a Nobel Prize in Chemistry 1964, making her the third woman to win the Nobel. She was named by Queen Elizabeth II as a member of the Order of Merit, the United Kingdom's highest royal order, in 1965.

Without Dorothy Crowfoot Hodgkin's pioneering techniques and contributions to structural biochemistry, it is doubtless that the field would not be as advanced as it is today.

External links

• http://nobelprize.org/nobel_prizes/chemistry/laureates/1964/hodgkin-bio.html
• http://www.sdsc.edu/ScienceWomen/hodgkin.html
• http://www.chemheritage.org/discover/chemistry-in-history/themes/molecular-synthesis-structure-and-bonding/hodgkin.aspx
• http://www.sjsu.edu/depts/Museum/hodgki.html

Albert Claude (August 23, 1899 - May 22, 1983), who was a Belgium biochemist who specialized in the structure and function of cells was born in Longlier, Belgium and is most well known for winning the Nobel Peace Prize in Physiology and Medicine 1974 with Christian de Duve and George Emil Palade "for their discoveries concerning the structural and functional organization of the cell." Albert Claude made giant strides for cell biology in his studies of the cell structure.

Claude was born and buried in Belgium but was also a U.S. citizen. He served in World War I with British Intelligence and later received the Inter-Allied Medal for his contributions and was admitted into the University of Liege through a program for war veterans.

After receiving his medical degree in 1928, he joined the Rockefeller Institute for Medical Research in New York in 1929 and became an American citizen. In 1930 Claude discovered the process of cell fractionation. This was groundbreaking at the time because prior to Claude's research, it was thought that the inside of cells were composed of a chaotic mass of substances with no order or particular function. However, with his discovery, Claude was able to show that cell interiors are in fact very well-organized. To discover cell fractionation, Claude used mechanisms from everyday machinery. He combined the mechanism from meat grinders and a sieve to construct a simple, high-speed centrifuge which led the way for ultracentrifugation, a technique for breaking and spinning infected cells to isolate their agents according to mass. He discovered that particular fractions of the cells correlated to particular cell functions. Claude discovered the endoplasmic reticulum, which is a membranous network within a cell. The rough endoplasmic reticulum, which has ribosomes attached to the surface, synthesizes proteins. The smooth endoplasmic reticulum synthesizes lipids and steroids, metabolizes carbohydrates and steroids (but not lipids), and regulates calcium concentration, drug metabolism, and attachment of receptors on cell membrane proteins. Claude is also coined as one of the first scientists to have used an electronic microscope for his cellular structure studies.

In 1948, he returned to Belgium where he was the dictator of the Jules Bordet Research Institute. He then went on to retire in 1972.

References

http://www.answers.com/topic/claude-albert http://encyclopedia2.thefreedictionary.com/Albert+Claude Christian de Duve is a renowned biochemist and cytologist. De Duve was born on October 2, 1917 near London but being of Belgian descent, moved back to Antwerp,Belgium where he was educated by the Jesuits and later went to school at the Catholic University of Leuven. He is most well known for his studies in subcellular biochemistry and cell biology. He was attracted to studying medicine because of the appeal of having an occupation in the field of medicine.

He first started off his career in a laboratory under Professor J.P. Bouckaert, who greatly influenced his later career. De Duve's work in the laboratory was focused on discovering the effects of insulin upon glucose uptake in the body; therefore, by the time he graduated, de Duve's main primary goal was to elucidate insulin's mechanism of action. From that point on, his career was focused on the biochemical study of insulin.

He eventually became a professor in 1951 at Louvain, and headed a small research laboratory to answer the broader questions concerning insulin. In this lab, he accidentally discovered the "latency" of acid phosphatase while investigating carbohydrate metabolism in the liver. He abandoned his insulin focus, and decided to focus on his new discovery instead. Following this new focus in his career, de Duve was coined for discovering lysosomes and peroxisomes, cell organelles where digestive and metabolic processes take place. He found that lysosomes are the cell's digestive system, while peroxisomes are where crucial cell metabolism takes place.

In 1962, de Duve became a professor at Rockefeller University in New York and started another laboratory with the same general research interests as the first laboratory in Belgium. In 1974 he was awarded the Nobel Prize with his colleagues Albert Claude and George Palade for describing the structure and function of organelles in cells. In addition to contributing to the discovery of the structures inside cells, he studied the enzyme activity in rat liver cells using a process called rate-zonal centrifugation. These studies helped pave the way for further discovery into the function of cell structures.

Venkatraman Ramakrishnan at 2009 Nobel Prize Press Conference

Venkatraman Ramakrishnan is an Indian-born American Structural Biologist. Born in Chidambaram in Cuddalore district of Tamil Nadu, India, he spent his life with his highly educated parents. His father headed the biochemistry department at the Maharaj Sayajirao University in Baroda and his mother obtained a Ph.D in psychology. When his mother could not find a position in Baroda's psychology department, she helped his father in his research instead with fellow scientists. They eventually collaborated in their work and greatly influenced Ramakrishnan's scientific interest from a young age.

Through the influence of both his parents, Ramakrishnan became interested in science as a young student, which led him to partake his undergraduate studies in Physics at the same university his parents taught at, Maharaj Sayajirao University in Baroda. He also credits his interest in science being due to a few inspiring teachers and professors from his childhood and his college years.

After not getting accepted to the Indian Institute of Science he moved to USA where he obtained a Ph.D. in Physics from Ohio University. After completing his graduate studies at Ohio University, he then spend two years studying biology at the University of California, San Diego. While there, Ramakrishnan became interested in ribosomal work while in a lab researching lipid bilayers. He was then offered a postdoctoral position at Don Engelmen and Peter Moore's lab working on a ribosome project involving membrane proteins. His work at Moore's lab taught him the valuable techniques for purifying, reconstituting, and assaying ribosomes, which he would later use to study the structure of the 30S subunit (which would win him a Nobel Prize). It was at this lab that Ramakrishnan first started to map the locations of proteins in the 30S subunit by reconstituting ribosomes where proteins were replaced by deuterated counterparts, as well as learn to map out proteins using neutron scattering experiments at Brookhaven National Laboratory.

After an unhappy stay at Oak Ridge's Biology Division, Ramakrishnan found a new position at Brookhaven as a staff scientist where he worked on projects with ribosomes and chromatin. He obtained a tenure to focus on the study of crystallography while on a sabbatical to obtain knowledge to help further his study of ribosomes.

Through some hard work he was able to obtain a position at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England—this laboratory was the birthplace of crystallography. Before leaving to England, Ramakrishnan collected data for ribosomal protein S5 and multiwavelength anomalous diffraction data for crystals of selenomethionyl GH5. While on his sabbatical in England, he eventually solved the structures of both compounds using the data he brought with him. He eventually decided to move to the LMB to work on his ribosome problem. His focus switched entirely to the 30S subunit structure before this move and the proteins within it were later identified. In 2009, along with Thomas A. Steitz and Ada E. Yonath, won the Nobel Prize in Chemistry for their studies of the structure and function of the ribosome. Working with crystals and diffraction patterns, Fourier maps were calculated for the structure. The discovery of the 30S subunit structure led to an understanding of how ribosomes can ensure the accuracy of translation when a genetic message is being decoded. Currently established at the MRC Laboratory of Molecular Biology in Cambridge, England, his lab is interested in studying the structure and function of the ribosome, the large protein-RNA complex that synthesizes proteins using genes encoded in mRNA. His studies have opened new avenues in understanding antibiotic function, along with comprehending the mechanism of tRNA and mRNA recognition and decoding by the ribosome.

Roger Kornberg at Fairchild auditorium, Stanford

Roger David Kornberg was born in April 24th, 1947, and was the Nobel Prize winner of Chemistry in 2006 for his research in eukaryotic transcription.

Transcription is part of the Central Dogma in which DNA is transcribed into RNA and then translated into proteins. In DNA transcription, mRNA is transcribed by an enzyme called RNA polymerase II with the help of other proteins. In Kornberg’s research at Stanford University, yeast was used to determine the three-dimensional structure of a protein cluster of RNA polymerase II and other proteins. Identification of transcription machinery, to Kornberg, was necessary in order to further the study of transcriptional regulation. In addition, yeast was used because it was a unicellular organism that had the same RNA polymerase II system as mammalian systems. Kornberg first accomplished this by creating a technique to form a two-dimensional protein crystal on lipid membranes to produce a low resolution image of the RNA polymerase II. Later, he was able to use this technique to yield larger crystals that could be used in x-ray crystallography to determine the three-dimensional structure of RNA polymerase II on an atomic level. This technique was then applied to find the other accessory proteins that are associated with RNA polymerase II. He then used this information about the proteins to determine the transcription process of yeast by isolating purified forms of certain proteins in transcription. These discoveries in yeast, Kornberg was able to detect an additional protein that transmitted gene regulation signals to the RNA polymerase II that was named “Mediator”. The discovery of the “mediator” was, “a true milestone in the understanding of the transcription process” according to the Nobel Prize committee.

References

http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2006/kornberg-autobio.html

http://www.nndb.com/people/615/000138201/ Elizabeth Neufeld is most notable for her work in advances in treatment for genetically inherited diseases such as Hurler's, Hunter's, and Sanfilippo syndrome. She was born in Paris and later moved with her family to New York in 1940. She was a research assistant for Elizabeth Russell at Jackson Memorial Laboratory, and shortly attended the University of Rochester for her masters until her father passed a way. After getting married she found a technician position available in the department of biology at Johns Hopkins. She later enrolled in the graduate program at UC Berkeley in Comparative Biochemistry.

As her career developed she eventually studied Hurler's syndrome, an autosomal recessive inherited disease resulting in a multitude of effects including progressive mental retardation and leading to death by about age 10. The biological problem that occurs in those with Hurler's syndrome was known to be associated with the storage and excretion of mucopolysaccharides, though the specifics had yet to be determined. Patients fibroblasts, synthesizing cells found in connective tissue, showed irregular accumulation of mucopolysaccharides. At first Neufeld thought it to be a problem of overproduction, though her experiments revealed that it was in fact a result of insufficient degradation.

After Danes and Bearn published a paper postulating that normal cells assist mutant cells with mucopolysaccharide degradation, Neufeld's partner had a mix up in Hunter's and Hurler's cells in the lab. Keeping this plate with the mixed cells, he and Neufeld discovered that the cells in fact underwent some normalization! The cells appeared to be secreting 'corrective factors' in mixtures of different genotypes. The corrective factor was found to be α-L-iduronidase. Hurler factor has α-L-iduronidase activity, but it is deficient. While Neufeld's group was looking for the uptake signal, a researched named Sly found that mannose-6-phosphate was the recognition signal for lysosomal enzymes while studying a disease with β-glucuronidase deficiency--another mucopolysaccharide storage disease.

With these key pieces of knowledge, Neufeld and fellow researches sought therapy for those with Hurler's syndrome. Meanwhile, Robert Shull who found signs of lysosomal storage diseases in a Plott hound, sent Neufeld fibroblasts which ended up being α-L-iduronidase deficient. Shull then started a colony of this dog to understand more about this disease, and created an animal model for enzyme replacement therapy. Using cDNA of α-L-iduronidase, Neufeld teamed up with Emil Kakkis and used Chinese hamster ovary cells to make recombinant human and canine DNA, which successfully excreted the enzyme with the M6P signal and was highly corrective! This cDNA was used in α-L-iduronidase deficient dogs and found to be effective! After short and long term trials with dogs, then 55 human trials, the FDA approved the treatment in 2003 for Hurler's syndrome. It was later approved for other mucopolysaccharide storage diseases.

Neufeld spent 35 years of her life developing a treatment for the rare lysosomal enzyme disease. Thanks to her, enzyme replacement therapy for alpha-L-Iduronidase deficiency is now an acceptable treatment. Using the mannose 6-phosphate system, the therapy is now being used to treat Hunter and the Maroteaux-Lamy syndromes.

Despite the acceptability of enzyme replacement therapy, there are still many issues. One major issue is that this is a highly expensive treatment, both for administration, and for further research. Another major restriction in this treatment is that not all of the human body is equally receptive to the new enzymes. For example, especially in the central system, intravenously injected enzymes are blocked by the blood-brain barrier. This is rather unfortunate as many patients with mucopolysaccharide storage diseases have neurologic variations. Though research has been done for alternative administration methods, and other possible pharmaceuticals to correct the enzyme misfolding, as of right now, only the alternative administrations have been brought to clinical trials. Thus it may be many years before the problem is fully solved.

Tranplantation of hematopoietic stem cells from bone marrow or cord blood may be another therapy for Hurler syndrome, but it is still a risky procedure. Additionally, it is thought that there might be a "takeover" with the donor's cells gradually replacing the patient's cells.

Since her successful efforts in therapy for Hurler's syndrome, Neufeld has received the Javits Award for her work on Tay-Sachs disease, and is now interested in Sanfiippo Syndrome. Each type of Sanfilippo syndrome has a lysosomal enzyme deficiency, and Neufeld discovered the syndrome to be a tauopathic disease-- a group of neurodegenerative diseases which all lead to dementia. She found that the expression of many mRNAs changed in the experiments, the mRNA encoding lysozyme stood out as it was elevated over 6 times the normal in both the affected and control areas in MPS IIIB mice. Immunohistochemistry demonstrated that the lysozyme protein was elevated only in the medial entorhinal cortex. Lysozymes have been studied for a long time, and in fact was one of the first enzymes to be studied, and was discovered to be a product of phagocytes an epithelial cells by Alexander Fleming. However, it had not yet been described in neurons. Neufeld proposed that the elevated levels of the lysozyme in the medial entorhinal cortex could induce hyperphosphorylated tau.

Neufeld hopes that research into Alzheimer's (another disease in the tauopathy family) will also lead to advancements in understanding and treating Sanfilippo Syndrome.

Annu. Rev. Biochem. 2011.80:1-15. Download from www.annualreviews.org by University of California - San Diego on 11/10/11. For personal use only.

Introduction

Professor Ivan Berke was the founder of the clinic enzymology and medical biochemistry in Serbia and Yugoslavia who played an important role in pharmacy and medicine. Many students under his tutorship became biochemists who specialized in my different fields. His contribution will help many new generations in the medical field. He was a role model to all of his students in every aspect.

Biography

Professor Ivan Berke was born on November 13th 1910 in Bjelovar. In 1933, he graduated from a Pharmacy Department in Zagreb. In 1936, he graduated from the 7th group of Chemistry In Zagreb. He then served in military for one year. In 1939, he obtained a doctorate in chemistry and was elected to become an assistant at the Chemical Institute of the Faculty of Medicine. After holding several positions at the Institute of Chemical, he then became director of that Institute. He became a scientific advisor in Budapest and then worked for the Institute of Chemistry in Zagreb until 1953. During 1953 and 1960, he was an Associate Professor of Biochemistry at the Medical Faculty in Skopje. In 1960, he joined the Biochemistry Institute in Belgrade. Later in 1964, he was elected as a Senior Professor of Biochemistry and remained at this position until retirement in 1978.

Academic Career and Contribution

Professor Ivan Berkeš, an important figure in the field of pharmacy and medicine, was the founder of medical biochemistry and clinic enzymology in the health care of Serbia and Yugoslavia. Under his guidance, many generations of medical biochemists were educated at the Faculty of Pharmacy in Belgrade, and for a long time there was no laboratory in Serbia that did not employ one of Prof. Berkeš’s students. Prof. Berkeš founded Serbian medical biochemistry and established it as a scientific and health discipline. His work will live on through these and the future generations of medical biochemists, who remain eternally grateful and promise to honor his memory with love and respect.

Prof. Dr Ivan Berkeš was born on November 13th, 1910, in Bjelovar, where he was educated at the Classical Gymnasium (studying Latin and German for 8, and Greek for 6 years). In 1933 he graduated from the Department of Pharmacy of the Faculty of Philosophy in Zagreb. It should be mentioned that he completed his internship at the Pharmacy of Stanislav Ilakovac in Zagreb, having taken the following classes during the course of his studies: Physics with Prof. Hondl, Botany with Prof. Vouk, Chemistry with Prof. Bubanovic, Pharmacognosia with Prof. Vrgo~, Pharmaceutical Chemistry with Prof. Fluniani and Pharmaceutical Technology with Prof. Benzinger. In 1936 Ivan Berkeš also graduated from the 7th group of Chemistry (a. Chemistry, b. Experimental Physics, c. Physical Chemistry, Higher Mathematics, Mineralogy and Botany) at the Faculty of Philosophy in Zagreb.

Ivan Berkeš obtained a doctorate in philosophy (namely, chemistry) in 1939 at the University in Zagreb. That same year, he was elected as an assistant at the Chemical Institute of the Faculty of Medicine, whose head at the time was Prof. F. Bubanovic. In 1941, Dr Ivan Berkeš was dismissed from employment and the following year imprisoned at the concentration camp Kraljevica-Rab. From 1943 to 1945 he was actively involved in the National Liberation War. After the war, between 1945 and 1947 Dr Ivan Berkeš held various functions at the state Institute of Chemical-Pharmaceutical Production in Belgrade, serving as the assistant director and later director of this Institute. In the period of 1947–1948 he worked as a scientific advisor for the Reparation Committee in Budapest, after which he rejoined the staff of the Institute of Chemistry of the Faculty of Medicine in Zagreb, where he worked until 1953. Between 1953 and 1960 Dr Ivan Berkeš taught at the Medical Faculty in Skopje, where he had been elected as an Associate Professor of Biochemistry. In that period he formed the Biochemical Institute at this Faculty. In 1960 Dr Ivan Berkeš joined the Institute of Biochemistry of the Faculty of Pharmacy in Belgrade. He was elected Senior Professor of Medical Biochemistry in 1964, and remained at this faculty, as a long-term director of the Biochemistry Institute, until his retirement in 1978.

His contribution in scientific work was first influenced by Tomislav Pinter, who explained to him about how analytical and physical chemistry worked. In 1931, with the help of professor Milo Mladenovic, he then became more interested in preparative organic chemistry and Pregl’s micro-analysis. After that, he focused on determining the functional groups of polyterpene acid in a-elemi and b-elemonic acids. This work led to the first papers about the new derivatives of dihydro- and dribromineelemonic acid, and di- and tetrazonide. With the help of Dr Pinter, he focused more about inorganic analytics.

He was the one who created a basis for electrophoresis. This technique became a main focus on clinical biochemistry. Due to financial problems to use the large apparatus in the lab, Dr Berkeš introduced some methods of solutions for paper electrophoresis. Later then, he was one of the greatest investigators in this field and his works were cited in everything that dealt with this topic.

Besides many applications of this electrophoresis, the most interesting study was of nephritic syndrome in children in 1952. Dr Berkeš spent several years developing “Thiol Function” in Serbia which led to his achievement in determining the activity of enzyme dimethyleethine: homocysteine methylferase.

He spent most of his time doing methodological research in biochemistry and enzymology. He became more and more interested in enzyme and finally ended up with this famous book “General and Medical Enzymology”. He was a tutor for 18 years during the time he was in Belgrade. More than 150 students under his guidance became biochemists who specialized in my different fields. Throughout his life, he had published many books and articles all over the world.

He authored over 200 papers in international and national journals, as well as of several books.

Upon his death, in 1997, his former students gathered in the Society of Medical Biochemists of Serbia, established the Scientific Foundation "Professor Ivan Berkeš". The Foundation traditionally awards the best students graduated at the Faculty of Pharmacy University of Belgrade and organize the Annual Scientific Conference where the doctoral dissertations defended in the field of medical biochemistry during the past year are presented.

Reference

Biochem, J.Med, . "Journal of Medical Biochemistry." Journal of Medical Biochemistry. 30.2 (june2011): 160-166. Print. James C. Wang is a biochemist who had taught at Harvard University and University of California, Berkeley. He is the person who discovered DNA topoisomerase, which was a new enzyme at that time that was able to convert a DNA ring from one form to another. After its discovery, researchers and scientists were able to study how DNA strands and double helixes were passed from one another.

Early Life

Wang was born in the Jiangsu Province of China during a time of war and tension between China and Japan. Although his time in school was constantly being interrupted, he received a decent education from his mother and through self-learning. Majoring (graduating) in chemical engineering at the National Taiwan University, he continued to pursue his love for chemistry working as a lecturer after graduation. He continued his education and received his PhD in Physical Chemistry at the University of Missouri. Soon after, he received a position to work with DNA alongside with Norman Davidson at the California Institute of Technology in 1964.

Discovery

While Wang was working with DNA, he started to question why isolated DNA rings were negatively supercoiled. Back then, scientists answered this questions with two different models - one, because the helical structure of DNA inside and outside a cell were different; or two, because of the unique structure within an intracellular DNA where the two complementary strands were kept apart. In other words, the first model suggested that an increase in the number of negative supercoils correlated with its size, while the second suggested that the number of negative supercoils would be independent to its size. Wang decided to look into these two models under identical conditions and discovered that a 25-fold range would have a 1.5 factor of negative coils per length.

In an accidental discovery, Wang left centrifuge tubes containing lysate with infected E. coli cells unattended only to come back with relaxed DNA rings 2.5 hours later. From that small incident, Wang later discovered that supercoiled removal activity and DNA ligase did not correlate with each other. Instead, the "w" protein was the one that removed negative supercoils.

The 1970s was a time of breakthrough regarding DNA research. James Champoux and Renato Dulbecco discovered an activity in mouse cell that relaxed both negative and positive supercoiled DNA with the presence of Magnesium in 1972, and in 1976, Martin Gellert discovered an E. coli enzyme that catalyzed ATP-dependent DNA (DNA gyrase). In 1979, Wang named these enzymes "topoisomerase" because of their ability to interconvert topological isomers. From there, he was also able to prove that positively supercoiled DNA can be relaxed if a short single-stranded loop is inserted into the DNA.

References

http://www.annualreviews.org/doi/pdf/10.1146/annurev.biochem.78.030107.090101 Professor Nobuhiko Katunuma (1926-November 11, 2013) was one of the world’s leading scientists specialized in proteolysis in general and cysteine proteinases and their corresponding inhibitors in particular. As a renowned scientist, Professor Katunuma’s research interest is related to the medical and biomedical field as his great uncle, Professor Seizo Katsunuma, the President of Nagoya University, had told him ‘Biochemists working at Medical Schools should contribute in the fight against diseases in man’. His scientific contribution was rewarded with the ‘1990 National Violet Ribbon Decoration for Scientists and Artists’ award. Besides being a successful researcher, Professor Katunuma is also an inspirational colleague and dedicated mentor. His passion for science and intrigued ideas always provoke his coworkers. He usually observes his students’ experiment closely and also involves himself in these experiments to enhance his scientific sense even further. Nowadays, more than 30 researchers who had been Professor Katunuma’s mentee have become Professors or Laboratory Heads or even established their own laboratory. Outside his love for structural chemistry, Professor Katunuma is also interested in photography, music and Kendo, or Japanese sword fencing.

Biography

Professor Nobuhiko Katunuma was born in 1926 in Nagasaki, Japan. He graduated from the School of Medicine at Nagoya University in 1953. After earning his Doctor of Philosophy in medical sciences, he completed his Postdoctoral with Professor Hugo Theorell at the Nobel Institute in Stockholm, Sweden. After that, he moved back to Japan and became an Associate Professor at the Institute of Protein Research, Osaka University. In 1963, he moved to the Institute of Enzyme Research, School of Medicine at Tokushima University. With his widely successful scientific career and dedication to young researchers, Professor Katunuma was promoted to be the Director of the Institute since 1971 and also served as Dean of the Medical School at Tokushima University from 1980 to 1982. In 1992, he retired from Tokushima University and continued his research at the Institute for Health Sciences, at Tokushima Bunri University.

Academic Career

During the first 30 years at Tokushima University, Professor Katunuma’s main research was about the enzymes involved in vitamin B6 metabolism and their intracellular protein turnover. Together with his colleague Mitsuko Okada, he discovered mitochondrial glutamicoxalacetic transaminase and the urea cycle glutaminase isoenzymes. Later on, with his colleague Yasuhiro Kuroda, he established the enzymes’ functions in the hepatocarcinogenesis.

In 1971, he discovered the acceleration of pyridoxal enzyme turnover in animals with vitamin B6 deficiency and the enzymes participate in proteolysis of the apoproteins. These discoveries suggested that protein degradation can be initiated by the apoprotein formation in proteolysis process. This idea provoke further research into the initiation of various biochemical pathways by limited proteolysis, such as prothrombin activation by mast cell tryptase histamine release by mast cell chymase, and initiation of influenza virus entry by tryptase Clara. In his later years at Tokushima University, he also conducted a research project specialized in the role of lysosomal enzymes and their inhibitors in intracellular proteolysis. His studies on the 3D structure of protease enzyme cathepsin B in human in collaboration with Robert Huber led to his subsequent studies on chemically designed specific-inhibitors against enzyme cathepsins. With these studies, Professor Katunuma established himself as one of the pioneers in the field of structural based drug synthesis.

In 1992, after his retirement from Tokushima University, he started his second career as Professor and Director of the Institute of Health Sciences in Tokushima Bunri University. In his new position as the President of Tokushima Bunri University, Professor Katunuma actively involved in the development of new synthetic cysteine protease inhibitors, the derivatives of E-64 and the CLIK inhibitors, and studied the role of cysteine proteases in bone resorption.

Reference

Kido , Hiroshi, and Kazumi Ishidoh. "Journal of Biochemistry." Journal of Biochemistry. 148.5 (2010): 527-32. Print. Matthias Hentze is a German scientist born January 25, 1960. He is the Associated Director of the European Molecular Biology Lab and Professor of Molecular Medicine at Heidelberg University. Had medical training in Germany and the United Kingdom. In 1884, he received his medical degree from the University of Munster in Germany. In the late 1980s did his postdoc at the National Institutes of Health in the United States, where he and his colleagues discovered 'iron-responsive elements'. Along with his career in science, Hentze is also a marathon runner, and claims that once marathon running became a part of his life, long days no longer wear him down.

While doing his postdoct at the National Institutes of Health, Hentze and colleagues discovered 'iron-responsive elements'. This caught his interest in post-transcriptional gene regulation and the diseases of iron metabolism. This interest was the result of a failed postdoctoral project in which Hentze cloned human ferritin genes to try and explain the elusive genetic defect in hereditary hemochromatosis. Within months of catching interest, they had showed that IRE's can regulate translation and mRNA turnovers. This laid the foundation of the first genetic regulatory network that is in cytoplasm.

Hentze co-founded as well as co-directs the Molecular Medicine Partnership Unit, which is a join interdisciplinary translational research unit between EMBL and Heidelberg University. This acts as a bridge between medicine biology and molecular biology. Hentze is a recipient of many national and international research honors such as Germany's highest research award, Gottfried Wilhelm Leibnize Prize. Hentze is an elected member of both the European Molecular Biology Organization and Germany Academy Sciences. With the ERC Advance Grant, Hentze group is exploring how metabolism and the gene regulations are coordinated.

Reference

• Hentze, M (2012). "An interview with Matthias Hentze". Trends in Biochemical Sciences. 37 (12): 507–8. doi:10.1016/j.tibs.2012.09.004. PMID 23047134.

Rosalind Elsie Franklin was famous for her research and discovery work for understanding the structure of DNA, RNA, viruses, coal, and graphite. She is best known for her work with x-ray crystallography and x-ray diffraction images of DNA which eventually led to the discovery of the double helix. She is most memorable for her contributions to the understanding of DNA. DNA is the foundation of genetics and the better understanding of its structure gives a better understanding of how genetics are endowed from parent to offspring. Although the research and images provided by her proved to be accurate and valuable in discovering the DNA structure, her contributions are often overlooked. Many of her unpublished drafts show that she located the phosphate groups of DNA. Unfortunately, Watson and Crick only hint at her contribution. In 1958, she died of ovarian cancer while leading research on the polio virus.

Early Life

Franklin was born on July 25, 1920 in Notting Hill London into an affluent family. Her father was a merchant banker at the time and her parents had five children, Rosalind being the eldest. According to her mother, Muriel Frances Waley, Rosalind always knew where she was going and at sixteen, she took science for her subject. At an early age, she demonstrated aptitude for maths and science and foreign languages including French, Italian and German.

In 1938, 18 at the time, Rosalind started her college career at University of Cambridge. Three years later, she was awarded a bachelor's degree and received a research fellowship with R.G.W. Norrish at the National Cancer institute. Afterwards, she continued to work as a research assistant at the British Coal Utilisation Research Association (BCURA) with professor Norrish. She based her Ph. D. thesis on the porosity of coal, and after she wrote The Physical Chemistry of Solid Organic Colloids with Special Reference to Coal and five other papers, Cambridge University awarded her a Ph. D. in 1945.

Discovery

In 1951, she started working with John Randall at the King's College London. She worked on DNA fibers and experimental diffraction. Here, she was able to increase her skills with x-ray diffraction. In Randall's lab, she was partnered with Maurice Wilkins. Although they were both concerned with DNA, they led separate research groups and projects. Although the university was not very welcoming for women, Randall persisted on the DNA project and utilized her knowledge in x-ray crystallography to see different images of the DNA.

Franklin was an X-ray crystallographer. Her images of the x-ray diffraction of the DNA molecule led to a better understanding of the DNA structure. Her work had confirmed that the DNA is of a helical structure. She had purposed that there are two types of the DNA molecule, type A and type B. Furthermore, she determined the location of the phosphate groups and insisted that the backbones were on the outside of the structure.

Although she was very close to solving the complete structure of DNA, Watson and Crick beat her to the finish due to many bickers with Wilkins and herself. It is known that at one point, Wilkins showed Watson one of Franklin's x-ray portraits of the DNA and this served as the last missing puzzle piece for Watson and Crick.

Controversies

Although Franklin's work was mentioned in the published journal written by Watson and Crick, the amount of credit she deserves still remains questionable. There is no doubt that her data were used by Watson and Crick to build their model of DNA in 1953. Although she did have a meaningful role in proposing the structure of the DNA, many people argue that Watson and Crick already figured out the model on their own and that her portrait just 'confirmed' what they already knew. Instead of inviting Franklin to co-author their paper describing the structure, Watson and Crick invited Wilkins, who leaked Franklin's portrait to Watson, to co-author. Although Wilkins declined this offer, he later expressed his regret of denying this offer. She was never nominated for a Nobel Prize because she died of cancer in 1958. Instead, the prize subsequently went to Watson, Crick, and Wilkins. It was extraordinary that her data was shown without her knowledge to researchers at another institute and Watson and Crick later admitted that without that data they could not have completed the proof of their model.

References

http://profiles.nlm.nih.gov/ps/retrieve/Narrative/KR/p-nid/187

http://www.sdsc.edu/ScienceWomen/franklin.html

Introduction

Shigeru Tsuiki

Shigeru Tsuiki was one of the pioneers in the research fields of complex carbohydrates and protein phosphatases. In 1951, after graduated from the Tohoku University Medical School of Japan, he began his career as a biochemist by working in the laboratory. Five years later, he had a chance to visit Dr Ward Pigman- a professor at the University of Alabama Birmingham Medical School after getting his PhD degree, and his contribution began from here. During his prominent career, he accomplished three different outstanding contributions to the biochemistry research field: with the method of purifying mucin from bovine submaxillary glands, identification of four different molecular species of mammalian sialidase, and an establishment of molecular basis for mammalian protein phosphatases.

Mucin Purification

During his visit to one of the leading society of American chemist, he developed an impressive method of mucin purification from using cetyltrimethylammonium bromide. This development greatly contributed to the characterization of peptides structures of mucin. After researching deeply and thoroughly into sialic acid components of mucin, this led him to study the enzyme which involved in sialic acid. He began to focus on the two key enzymes: glutamine-fructose-6 phosphate amidotransferase, and UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase UDP-GlcNAc and CMP-N-acetylneuraminic acid. After seeing different behaviours of these two enzymes during rat liver development, he found out that UDP-GlcNAc 2-epimerase could be obtained from rat liver.

Identification of four different molecular species of mammalian sialidase

At that time, most scientists knew that the removal of sialic acid residue from glycoprotein and glycolipids was the first step in the catabolism of glycoconjugates. With his passion for biochemistry, he continued to develop the four types of sialidase with differences in enzymatic properties and intracellular localization: intralysosomal, cytosolic and membrane-associated sialidases I and II. He experimented this development on rat, and his result showed that some of the tissues in rat contained all these four types.

• Intralysosomal sialidase- contains narrow substrate specificity.
• Cytosolic sialidase- hydrolyse glycoproteins and gangliosides.
• Membrane-associated sialidase I: not often hydrolyse with other substrates.
• Membrane-associated sialidase II: actively hydrolyse on glycoproteins and gangliosides as cytosolic sialidase.

Establishment of molecular basis for mammalian protein phosphatases

His last major contribution was the study of protein phosphatases. With the interest in biochemical research, he showed that the cellular glycogen content was controlled by itself, and this led him to protein phosphatases. Scientists have found out that the enzyme that was responsible for glycogen synthesis was glycogen synthase (GS), and for glycogen degradation was glycogen phosphorylase (GP). Both enzymes functioned differently: GP catalyses the phosphorolysis of glycogen, and GS catalyses the transfer of glucose from UDP to primer. Based on this information, Dr. Tsuiki investigated the enzymatic properties of the rat liver GS phosphatase. He came up with a way to solubilize rat liver GS phosphatase from glycogen using column chromatography. This method let us know the activity of GS phosphatases by increasing the GS in the absence of glucose-6-phosphate. With the success of carrying out this experiment, Dr Tsuiki began to work on his GS phosphatase project. His strategy was to use column chromatography instead of rat liver extract in order to purify protein phosphatases. The chromatography on DE52 column revealed one major difference in elution profile between GS and GP phosphatases activities. They showed three different peaks IA, IA, and II represented for three distinct proteins.

References

Biochem, J. Biochem. "Journal of Biochemistry." Journal of Biochemistry. 2011

File:Paulboyer.jpg

Paul D. Boyer

Paul Delos Boyer (born July 31, 1918) is a professor emeritus at the University of California, Los Angeles in biochemsitry as well as the 1997 Nobel Prize of Chemistry winner for his work with ATP (adenosine triphosphate) synthesis.

Early Life

Paul D. Boyer was born in Provo, Utah to Dell Delos Boyer and Grace Guymon. Although raised in an area with a strong Mormon community, Boyer was considered non-practicing. Because many of his developing years were spent during the Great Depression, Boyer learned early on the meaning of hard work and perseverance towards a goal. He attended Provo High School, where through his continued service on the debate team and student government, he eventually became the senior class president. Upon graduating from his high school as valedictorian, Boyer attended Brigham Young University, where he received a B.S. in chemistry. It was here that he met his wife, Lyda Whicker, whom he married on August 31, 1939, five days before they would leave for Wisconsin for Boyer to start his graduate studies.

Research Career

University of Wisconsin

Boyer enrolled at the University of Wisconsin, Madison in the outstanding biochemistry department. It was here that he really developed an interest in enzymology and metabolism, which would eventually become his main research focus. Because of the new biochemistry wing that had just finished construction, Boyer had the opportunity to attend symposiums on biochemistry from some of the great biochemical minds of the time.

Stanford University

Upon being granted his Ph.D. in 1943, Boyer headed to Stanford University to work on a war project. Here he studied albumin serums from blood plasma that were used to treat shock on the battlefield. The problem with these serums was that upon being heated to kill viruses and microorganisms, the solutions would be come cloudy and the proteins denatured. This was where the research was needed to improve the serum to the point that the proteins would remain stable even under heat. Eventually, Boyer and his team discovered that long chain fatty acids stabilized the serums significantly better than any other compounds, and that these fatty acid chains could even reverse denaturation in some cases.

University of Minnesota

The next phase of Boyer's career would take him to the University of Minnesota, where he was offered an Assistant Professor position because of his work at Stanford. Here, he focused his research on biochemistry, more specifically enzymes. He eventually had the opportunity to accept a position on the Guggenheim Fellowship in 1955, allowing him to work in Sweden with Nobel Prize winner Hugo Theorell. That same year, he was awarded the Award in Enzyme Chemistry by the American Chemistry Society. He took up a professorship at the medical school at the University of Minnesota, and spent much of his research time on enzymes again. While his research was not yet focused on the ATP synthase that would eventually win him the Nobel Prize, he had a keen interest in the subject and worked with oxidative phosphorylation pathways whenever he had the chance.

UCLA and the Molecular Biology Institute

In 1963, Boyer and a select group of graduate students were sent to Los Angeles to open a new wing of the chemistry building at UCLA. It was on this trip that the allure of California became too much for Boyer to ignore anymore, and in 1965, he became the director of the Molecular Biology Institute (MBI) at UCLA. On the trip in 1963, Boyer discovered that phosphohisitidine was not a key to oxidative phosphorylation, but actually an intermediate in substrate level phosphorylation. This discovery, as well as his newfound resources available at the MBI led him to discover the binding charge mechanism for ATP synthesis. Despite discovering this in 1963, it took many years before it would be come generally accepted in the science community, and it took even longer for him to win his Nobel Prize, in 1997.

Post Research and Retirement

In 1990, Boyer became a professor emeritus at UCLA. He has a house near campus, where he and his wife live. They have three children, and eight grandchildren. The grandchildren who went to UCLA have stayed at his house during their time at the school.

References

• Paul D. Boyer at Encyclopædia Britannica
• http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1997/boyer-autobio.html
• http://www.chem.ucla.edu/dept/Faculty/boyer.html

Introduction

Maria Manaseina

Maria Mikhailovna Manasseina-Korkunova (1843–1903), also known as Marie von Manassein and Marie de Manacéine, was one of the pioneer in physiological chemistry and experimental somnology at the beginning of 20^th century.

Personal life and Career

Maria M. Manasseina was a daughter of Professor Mikhail Andreevich Korkunov (1806–1858, a famous Russian historian and archeologist. With excellent education received from her father, Maria Manasseina became one of the first women in Russia to obtain a degree of Doctor of Medicine. Her first marriage was with Poniatovsky, who was arrested and died in a political exile. In 1865, she married her second husband, Vyacheslav Avksentievich Manassein (1841–1901), who was a professor at the Medical Military Academy and a publisher of the first Russian medical magazine.

In 1870–1871, Maria Manasseina started to study the process of alcoholic fermentation in the laboratory of Julius Wiesner (1838–1916) at the Polytechnical Institute in Vienna. While there, she made a discovery of paramount importance thus becoming a founder of the new science of physiological chemistry (now biochemistry). She stated that the process of fermentation is due to specific substances (unorganized enzymes) that could be isolated from yeast cells, but not the living yeast itself. These experiments contradicted with Louis Pasteur’s physiological theory of fermentation and confirmed the chemical nature of fermentation.

Alcohol fermentation process

Two decades later, an influential German chemist, Eduard Buchner (1860–1917), announced the same experimental results. Even though he was aware of Manasseina’s work, Buchner failed to make any reference to it. Manasseina attempted to stand up for her scientific priority but failed. She was not recognized as a pioneer of the chemical nature of fermentation while Buchner received the Nobel Prize in 1907, four years after her death, for the discovery of the chemical nature of fermentation.

After the publication of her paper on fermentation, Manasseina was invited to work in the Giessen laboratory of the great German chemist Justus Liebig (1803–1873), where she was able to pursue her career as a biochemist. However, due to family reasons, she could not accept Liebig’s invitation and had to return to St. Petersburg. After coming home, Maria Manasseina turned into a physiologist specialized in sleep science and began to work in the laboratory of professor Ivan Romanovich Tarkhanov, a friend of her husband Vyacheslav A. Manassein. In the late 1870s, due to their marital problems, Maria Manasseina left her husband for his friend Ivan Tarkhanov. However, their relationship did not last very long since the biographers of Tarkhanov wrote nothing about his scientific and personal relations with Manasseina.

Manasseina was an extremely diligent research all her life. She conducted various experiments humans and animals as well as wrote scientific papers, books, and a lot of abstracts for Russian medical journals.

References

M. Kovalzo, Vladimir. "Journal of the History of the Neurosciences." Journal of the History of the Neurosciences. 18.3 (2009): 312-19. Print.

Introduction

Frederick Sanger, a biochemist from England, was twice awarded the Nobel Prize in Chemistry for his work on protein sequencing and DNA sequencing.

Personal Life

Frederick Sanger was born on August 13, 1918 in Rendcombe, England to Frederick and Cicely Sanger. He was one of three children, and was heavily influenced by his father, a stark Quaker and medical practitioner. From 1932 to 1936 Sanger attended the Bryanston School in Dorset, which employed the Dalton system and supported liberal regime. After receiving his B.A. in 1939 from Cambridge University, he chose to stay and complete in pH.D in biochemistry in 1943 under Albert Neuberger, where he delved into the chemistry behind lysine, an amino acid. During his time at Cambridge Sanger, who is a strong believer in Pacifism, joined the Peace Pledge Union, where he met his wife Joan Howe, a student of economics at Newnham College.

Nobel Prize of 1958

After Sanger completed his education in 1943, he joined Charles Chibnall's research group, where he studied the amino acid composition of bovine insulin. His efforts proved successful as he determined the amino acid sequence of two polypeptide chains of insulin, suggesting that proteins do in fact have a definite chemical composition. By using the Sanger Reagent, or fluorodinitrobenzene he could hydrolyze the insulin into smaller peptide chains, which were fractionated by electrophoresis and chromatography. Those fragments were recognized by ninhydrin and appeared as fingerprints. Sanger determined a technique for ordering amino acids, and in 1958 was the recipient of the Nobel Prize in Chemistry for presenting the complete structure of insulin.

Nobel Prize of 1980

In 1977 Sanger developed the Sanger Method, or dideoxy chain method for sequencing DNA molecules. This breakthrough was significant as it allowed scientists to sequence long stretches of DNA rapidly and accurately, and eventually was utilized for sequencing the Human Genome. He shared his prize of determining base sequences in nucleic acids with Walter Gilbert and Paul Berg.

References

"Frederick Sanger." HowStuffWorks. N.p., n.d. Web. 21 Nov. 2012. <http://science.howstuffworks.com/dictionary/famous-scientists/biologists/frederick-sanger-info.htm>.

"Concept 23A Gene Is a Discrete Sequence of DNA Nucleotides." Frederick Sanger. N.p., n.d. Web. 21 Nov. 2012. <http://www.dnaftb.org/23/bio.html>.

"Frederick Sanger." Wikipedia. Wikimedia Foundation, 21 Nov. 2012. Web. 21 Nov. 2012. <http://en.wikipedia.org/wiki/Frederick_Sanger>.

Introduction

Edwin G. Krebs, an American biochemist, was awarded the Nobel Prize for his work with Edmond H. Fischer in finding how protein phosphorylation functions as a regulatory mechanism.

Personal Life

Edwin G. Krebs was born on June 6, 1918 in Lansing, Iowa. After his undergraduate studies at University of Illinois, he started his study in medicine at Washington University School of Medicine in St. Louis. There, he was licensed as a physician and gained experience in medical research and later became a medical officer in the Navy. After the Navy, he decided to study biochemistry rather than returning to hospital work. He decided to continue as a biochemist and became an assistant professor at University of Washington, Seattle. There, he met Edmond H. Fischer, who he worked with to discover how protein phosphorylation functions as a regulatory mechanism. Afterwards, he became the founding chairman of the Department of Biological Chemistry at University of California, Davis. He also became the Chairman of the Department of Pharmacology at the University of Washington.

Nobel Prize in 1992

After becoming an assistant professor at University of Washington, Seattle in 1948, Krebs met Edmond H. Fischer, who arrived there in 1953. Together they worked on how phosphorylase functions as an enzyme. Through their research, they observed the mechanism of phosphorylation and saw the interconversion that phosphorylase goes through, called the reversible protein phosphorylation. This mechanism works by having a kinase add a phosphate group from ATP to a protein. The protein conforms to begin its function in a biological process. After the protein finishes its function, a phosphatase removes the same phosphate group and the protein conforms to its idle form. Because Krebs and Fischer were able to describe this process that occurs in numerous metabolic processes, they were awarded the 1992 Nobel Prize.

Reference

"AN ACCIDENTAL BIOCHEMIST." Annual Reviews. 21 Nov. 2012. Web. 21 Nov. 2012. <http://www.annualreviews.org/doi/full/10.1146/annurev.biochem.67.1.0?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed>
"Edward G. Krebs." Wikipedia. Wikimedia Foundation, 21 Nov. 2012. Web. 21 Nov. 2012. <http://en.wikipedia.org/wiki/Edwin_G._Krebs>

Introduction

John Cowdery Kendrew (March 24, 1917 - Aug. 23, 1997) was an English biochemist who was awarded the Nobel Prize in Chemistry in 1962 for his work for pioneering the use of x-ray crystallography in determining protein structure and more specifically the structure of myoglobin.

Biography

Kendrew was born in Oxford, England to a Wilfred George Kendrew and Evelyn May Graham Sandberg. He obtained a BS in Chemistry at Trinity College in 1939 and later obtained his PhD also at Trinity College in 1949. After his BS, Kendrew researched on reaction kinetics in the Department of Physical Chemistry at Cambridge. As time progressed, his interests slowly became more biological and eventually he decided to work on the structure of proteins. In 1946, he met his future colleague with whom he'd later share his Nobel Prize with, Max F. Perutz, in the Cavendish Laboratory, the Department of Physics at the University of Cambridge.

Nobel Prize in Chemistry (1962)

The 1962 Nobel Prize in Chemistry was awarded to not only Kendrew, but also to his colleague Max F. Perutz for their achievement in successfully using X-rays to determine the structures of complex proteins. While x-ray crystallography at the time could be used to determine the structure of simple compounds with tens of atoms, it was unable to do the same for complex structures because it was near impossible to know which phase, the point in the cycle of waves, the X-rays were at when they formed a dot. Perutz solved this problem with the use of heavy atoms, more specifically mercury, and putting them into specific positions in a protein molecule. The atoms altered the intensity of the diffraction pattern in a manner allowing them to determine the location of the atoms which provided a reference point used to calculate the missing phase information. Perutz then used this method to determine the structure of hemoglobin, while Kendrew used this method to determine the structure of myoglobin.

References

"The Nobel Prize in Chemistry 1962 - Speed Read". Nobelprize.org. 4 Dec 2012 <http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1962/speedread.html>

Introduction

Researcher, scientist, biochemist, Selman Abraham Waksman (1888-1973) did research on soil microbes in hopes to isolate effective antibiotics. He was successful in discovering the existence and isolating antibiotic Streptomycin. In the years after that, he was able to isolate many other antibiotics that were able to treat many disease such as tuberculosis, and other infections that were resistant to Penicillin. In 1952, Waksman was awarded the Nobel Prize in Physiology or Medicine for his accomplishment in discovering streptomycin. This was considered the first antibiotic that was actively against tuberculosis. Waksman earned himself the title of "Father of Antibiotics"

Above: Selman Waksman in his Laboratory at Rutgers University

Early Life

Born in 1888 in the small rural Ukrainian town of Novaya Priluka, Waksman was surrounded by fields of rich soil. Although agriculture was abundant around him, Wakman did not do much farming. However, it did plant a seed of curiosity as to what was in the soils that gave so much nutrition and even remedies that helped people. So in 1910, he did what many of his relatives were doing- move to america. Again, moving to a small town, Waksman enrolled in a small college - Rugers College, while working on a small family farm. It was during these early years that he was exposed to bacteria, as he started working in a lab. Getting introduced to such cultures such as the actinomycetes, his interest in microbes in the soil was growing. Watksman graduated with a Bachelor of Science in Agriculture.

In 1918, Watkins received his Ph. D in Biochemistry from the University of California, Berkeley, and returned to Rutger's University where he continued to research on microflora.

Research and Discovery

Inspired by a fellow researcher, Rene Dubois, who worked in his laboratory and isolated soil bacterium, Streptococcus pneumoniae, Waksman was motivated to look beyond the pre-existing antibacterial organisms. So he and his team structured their research so as to inhibit zones of colones that isolated soil microbes. These were grown under many different conditions and tested. After many test and trials, Waksman and his team isolated Actinomyces antibioticus, which was part of the actinomycetes family. But soon it was found that the actinomycin that was excreted was extremely toxic to the experimental organisms.
His research did not stop here, he continued until finally in 1944, he was able to discover the existence of streptomycin. This along with more than 20 new substances (that includes neomycin) were isolated. It was Waksman that coined the term "antibiotics" along the path of his research for inhibitors of natural growth.

Above: Streptinomycin, an antibiotic drug for tuberculosis. Isolated in the laboratory of Selman Abraham Waksman at Rutgers University.

References

1. http://www.jbc.org/content/279/48/e7.full

2. Waksman, S. A., and Woodruff, H. B. (1940) The soil as a source of microorganisms antagonistic to disease-producing bacteria. J. Bacteriol.

3. Trial, Richelle. UCSD Bacteriology (Bimm 120) Lecture 10/30/2012 "Bacterial Development"

William H. Stein

Introduction

William H. Stein was awarded the Nobel Prize in Chemistry in 1972 along with Christian Anfinsen and Stanford Moore work on the ribonuclease molecule in the connection between the amino acid sequence and biologically active conformation and also contributions to the understanding of the connection between chemical structure and catalytic activity of the active center of the molecule.

Discovery

Of the three scientists that worked to earn the Nobel Prize, Afinsen showed that the reason for the conformational changes that occur in ribonuclease upon reaction can be determined from the sequence of amino acids that make it up. The three scientists together have determined the sequence of amino acids that make up the entire enzyme ribonuclease. Furthermore, Stein and Moore observed that the amino acids making up the active site have much higher reactivity and were able to uncover what the groups were that made up the active site and were able to give a detailed representation of it even before the entire structure of ribonuclease was determined. Through this, it is said that Stein and Moore led studies that uncovered the important relationship between the chemical structure of an enzyme and its activity as a catalyst.

Early Life

William Howard Stein was born on January 25, 1911 in New York City to Fred and Beatrice Stein. His father was a businessman who worked at the New York Tuberculosis and Health Association after retirement and his mother also helped the community by making the lives of impoverished children better in New York. Stein attended the Lincoln School of Teachers College at Columbia University and here, he developed his early interests in creative arts, music, and writing. It was also at this school where he had his first chemistry course. Next, he went to the preparatory school Phillips Exeter Academy, which was a challenging educational experience. From there, Stein went on to Harvard University where he graduated in 1933 as a chemistry major. As a graduate student, Stein continued to stay at Harvard University where he decided to study biochemistry instead of organic chemistry.

Accomplishments

Nobel Prize in Chemistry (1972) Member of Editorial Committee of the Journal of Biological Chemistry for six years (Chairman of the committee for three years) Member of Editorial Board of the Journal of Biological Chemistry in 1962 Associate Editor from 1964-1968 Chairman of US National Committee of Biochemistry Member of Council of the Institute of Neurological Diseases and Blindness of the NIH

Death

William Stein had a disease called Gullain-Barré Syndrome which is an autoimmune disease centered around the peripheral nervous system which rendered Stein paralyzed by 1971. He passed away from heart failure in 1980.

References

"Press Release: The 1972 Nobel Prize in Chemistry". Nobelprize.org. 6 Dec 2012 http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1972/press.html

"William H. Stein - Autobiography". Nobelprize.org. 6 Dec 2012 http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1972/stein.html Vaclaw Leonovich Kretovich- member of the Russian Science Academic was born on January 27, 1907 in Yalta, Russia. He was one of the pioneers in biochemistry research. Throughout his life, he had discovered and contributed many important fields in biochemistry.

Introduction

He was raised in the family that did business in wine-making. During his college, he worked as a laboratory assistant and as a chemist at the same time. He started his biochemistry career at the age of 24 after graduating from Moscow State University in 1931. His career started when he was selected to work in the Protein and Protein Exchange Research with the Lenin All-Union Academy of Agricultural Sciences at that moment. After this, he spent most of his life time working at the Institute of Biochemistry. He became a professor and started teaching and doing research in biochemistry. There were hundreds of students under his guidance succeeded in obtaining doctor of science and many of them are holding important positions in biochemistry field. Upon completion of all degrees, in 1962, he became a member of USSR Academy of Sciences with a hope in finding out the connection between: biochemistry of bread and grain, and the biochemistry of nitrogen fixation and nitrogen metabolism. This was his biggest contribution to the biochemistry field. . One can easily find out about all of his work by the book Nitrogen Assimilation and Metabolism in Plants. This book about him and his work has been the best book in biochemistry.

Career Life

The biochemistry of nitrogen fixation and nitrogen metabolism

He began the study of enzymatic complex of nitrogenase. After a series of studies, he and his coworkers found out about the role of molybdenum which played an important function in nitrogenase and nitro reductase. With this success, he came closer to the different point between the two most important enzymes of nitrogen-fixing microorganisms and nitrogen metabolisms. The ratios of these two enzymes depended mostly on the nitrogen source and they always competed with each other for molybdenum.

In his group, he worked with many other biochemists. Together with Z.G.Evstigneeva, they figured out the study of glutamine synthetase and glutamate dehydrogenase. He also worked with T.LAuerman to learn about the properties of glutamine synthetase and glutamate dehydrogenase in yeasts. He also studied the rold of hemoproteins in nitrogen fixation. There were many researches in leghemoblogin which was a myoglobin-like protein that led to the difference between nitrogen fixation and leghemoglobin; synthesis of leghemoglobin was impaired to a greater degree than other hemoproteins.

Kretovich and his teamwork research discovered a new enzyme which was metleghemoglobin reductase. This enzyme mainly functioned in reducing leghemoblogin and keeping physiological state. After a series of studies, they found out that this enzyme was not in nodulin even it belonged to plant origin. This discovery led the world to have a better understanding in metleghemoglobin.

He and his teamwork also researched in amino acid synthesis of lysine, valine, tryptophan, isoleucine in plants. This research pointed out some important keys:

• For lysine synthesis, it starts via diaminopimelic acid in plant, but it starts via aminoadipic acid in fungi.
• For valine and isoleucine synthesis, the keto and dioxy analogs became corresponding amino acids.
• For tryptophan synthesis, it starts via anthranilic acid and indole.

Biochemistry of Grain and Bread

Another emphasis that Kretovich did was to study the biochemistry of grain and bread. His work led to the discovery of factors that determining the grain respiration intensity. It also let us know how biochemical functions in the storage of grain and bread. There was a disease called septic angina that happened in some parts of Russia. By mastering biochemistry of grain and bread, Kretovich and his coworker figured out that this disease was caused by the grain that was covered under the snow. This toxic grain was under studied and the technique to cure this disease was developed. Kretovich also focused on the kinetic biochemistry of bread. By using the enzymatic preparation that was isolated from microbial cultures, he came up with a proposal to increase the quality of the bread.

Reference

Applied Biochemistry and Microbiology, 2007, Vol. 43, No. 3, pp. 233–236. © Pleiades Publishing, Inc, 2007

Introduction

Linus Pauling, an American biochemist, was one of the most prominent chemists in history. He is the only person to be awarded two unshared Nobel Prizes. He was awarded the 1954 Nobel Prize in chemistry "for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances." In 1962 he was awarded the Nobel Peace Prize "for his campaign against nuclear weapons testing."

Personal Life

Linus Pauling was born in Portland, Oregon on February 28, 1901. At the age of 16, he was admitted to Oregon State University, then called Oregon Agricultural College. During the last two years at school, he began working on the electronic structure of atoms and how they are bonded together. He focused his studies on physical and chemical properties of the atoms that substances were composed of, thus, he became one of the founders of quantum chemistry. In 1922, he graduated with a degree in chemical engineering and attended Caltech for graduate school. There, he researched using X-ray diffraction to solve the structure of compounds.

Structural Biochemistry

One of the many discoveries of chemistry that Linus Pauling contributed to is proposing an accurate structure of the secondary structure of proteins. In 1951, Pauling, along with Robert Corey and Herman Branson, proposed the alpha helix and beta sheet structures of proteins. They were able to do this from looking at the structures of amino acids and peptides and the peptide bond's planar nature. Pauling was also able to assume that the amount of amino acids per helix could be a non-integer number, which it is (3.7 amino acid residues per turn). Linus Pauling also studied enzymes and was one of the first to postulate that the transition state needs to be stabilized in order for the enzymes to complete a reaction. This helped root the understanding of enzyme mechanisms. He was also one of the first to figure out that the ability of antigens and antibodies to bind was due to complementary structures between the two.

References

"Linus Carl Pauling: A Biographical Timeline." Oregon State University. Web. 06 Dec. 2012. <http://lpi.oregonstate.edu/lpbio/timeline.html>
"Configurations of Polypeptide Chains With Favored Orientations Around Single Bonds." PMC. Web. 06 Dec. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1063460/>
"Linus Pauling." Wikipedia. Wikimedia Foundation, Web. 06 Dec. 2012. <http://en.wikipedia.org/wiki/Edwin_G._Krebs>

Natural products with carbon-phosphorus bond

Phosphonic and phosphinic acid are similar to phosphate ester and anhydrides with instead of carbon oxygen bond have the C-P-C bond. They are stable and can withstand harsh chemical treatments.

The first naturally produced phosphonate compound was 2-aminoethylphosphonate (AEP). AEP was found in phosphonolipids. Phosphonolipids are present in many protozoa, plants, bacteria and even humans. It was found they are formed through ingestion and not made by the body. These phosphonolipids have a fatty acid chain and different phosphonate headgroups. Studies have shown that phosphonates can affect metabolism although the effects and causes are not well understood. The synthesis of AEP from phosphonoenolpyruvate (PEP) is the shortest known pathway to produce natural phosphonates. This pathway requires only three enzymes: PEP mutase, phosphonopyruvate decarboxylase, and AEP transaminase

Fosfomycin aka: (1R,2S)-Epoxypropylphosphonic acid It is used for the treatment of acute cystitis (urinary tract infections) and gastrointestinal infections. It has activity against methicillin- vancomycin-resistant organisms. Fosfomycin works by inhibiting the activation of necessary enzyme, UDP-N-acetylglucosamine- 3-O-enolpyruvyltransferase (MurA) is needed for catalyzing the first step of cell wall synthesis. This is done by alkylation of the active site cysteine.

Major Points

• Phosphonates and phosphinates have similar function to phosphate esters or anhydrides or carboxylate groups in enzyme substrates.

• Reactions involved in the biosynthesis of fosfomycin, phosphinothricin, and FR900098 is highly studied in this field

• Phosphoenolpyruvate (PEP) mutase catalyzes the C-P bond-forming step in all naturally occurring phosphonates. Therefore, degenerate primers for PEPM can be used for the discovery of new phosphonate encoding gene clusters and hence new natural products.

• Given the current commercial use of phosphonates and phosphinates in medicine and agriculture, discovery of new naturally occurring compounds beyond the twenty or so currently known structures may provide an important untapped source of new products for human use.

Reference

Metcalf, William W., and Wilfred A. Van Der Donk. "Biosynthesis of Phosphonic and Phosphinic Acid Natural Products." Annual Review of Biochemistry 78.1 (2009): 65-94.

Taxis

Chemotaxis is a behavioral response to a chemical stimulus in which an organism moves either toward or away from the stimulus. A chemical that causes an organism to move closer to it is called an attractant, whereas a chemical that causes an organism to move further away is called a repellent.

Overview

Cells use a flagella motor to move about, either toward or away from an attractant. When the cell moves away from an attractant, the receptors send a signal that allows one or more flagella to switch rotation from counterclockwise (CCW) to clockwise (CW). When the rotation switch is spinning counter-clockwise the cell goes into a run in a single direction, usually toward an attractant, which is favorable. When the flagella motor is rotating clockwise, the flagella disrupts the run, causing the cell to tumble. Each tumble causes the cell to swims off in a new direction. A counter clockwise rotation allows the cell to move faster than when the cell tumbles.

The pattern of movement resulting from alternating swimming and tumbling is a “biased random walk” in which the cell sometimes moves randomly but overall tends to migrate toward the attractant. When no attractant is present, the movement results in a "random walk", tumbling more often.

Research of Bacterial Chemotaxis

Signal transduction in sea-urchin sperm chemotaxis

Intact flagellum is isolated and purified from bacterium such as E. coli. The structure of the E. coli is then determined through the electron microscopy. It is with this data that the structure and function of the flagella can be understood. Further research into the motility of the bacterial flagella revealed that there are several genes required to conduct chemotaxis called the che genes. Mutants that failed to conduct chemotaxis to a singular attractant were discovered by Jerry Hazelbaur and Bob Mesibov and called "specifically nonchemotactic mutants" (Adler 2011). These mutants were later used in tests to determine what chemicals were attractants and which were repellents.

Motile bacteria respond to environmental cues to move to more favorable locations. The components of the chemotaxis signal transduction systems that mediate these responses are highly conserved among prokaryotes including both eubacterial and archaeal species. The best-studied system is that found in Escherichia coli. Attractant and repellant chemicals are sensed through their interactions with transmembrane chemoreceptor proteins that are localized in multimeric assemblies at one or both cell poles together with a histidine protein kinase, CheA, an SH3-like adaptor protein, CheW, and a phosphoprotein phosphatase, CheZ. These multimeric protein assemblies act to control the level of phosphorylation of a response regulator, CheY, which dictates flagellar motion. Bacterial chemotaxis is one of the most-understood signal transduction systems, and many biochemical and structural details of this system have been elucidated. This is an exciting field of study because the depth of knowledge now allows the detailed molecular mechanisms of transmembrane signaling and signal processing to be investigated.

Che genes

John Armstrong worked with E. coli and discovered the first nonchemotactic mutants. The mutants were basically bacteria that did not exhibit any attracting or repelling response to a chemical stimulus. However, the bacteria were still motile. With further analysis, three che genes were found necessary for E. coli to undergo chemotaxis. Those che genes were cheA, cheB, and cheC. The che mutants were investigated further in another study by Jerry Hazelbauer and Bob Mesibov, which led to chemoattractants and chemorepellants.

Che genes are responsible for the Che proteins in the chemotaxis process, which comes right after the MCP (methyl-accepting chemotaxis protein) receptors that receive the chemical stimulus and before the flagella. The Che proteins perform “excitation” and “adaptation” processes. Four more che genes (cheW, cheY, cheZ, and cheR) were discovered that played an important role in bacteria chemotaxis. After the MCP receptors have received the attractant or repellant stimulus, cheA, cheW, cheY, and cheZ signals the flagella to perform excitation and cheB and cheR signals the flagella to perform adaptation. These che genes are found commonly among bacteria (ones that utilizes flagella for mobility and ones that utilizes pili for mobility) and in the archaea. (Adler 2011)

Hybrid Escherichia coli ColE1 plasmids carrying the genes for motility (mot) and chemotaxis (che) were transferred to a minicell-producing strain. The mot and che genes on the hybrid plasmid directed protein synthesis in minicells. Polypeptides synthesized in minicells were identical to the products of the motA, motB, cheA, cheW, cheM, cheX, cheB, cheY, and cheZ genes previously identified by using hybrid lambda and ultraviolet-irradiated host cells (Silverman and Simon, J. Bacteriol. 130:1317-1325, 1977), thus confirming these gene product assignments. The products of some che genes (cheA and cheM) appeared as more than one band on polyacrylamide gel electrophoresis, but analysis of partial peptide digests of these polypeptides suggested that the multiple forms were coded for by a single gene. Measurement of the physical length of the hybrid plasmids allowed an estimate of the amount of coding capacity of the cloned deoxyribonucleic acid, which was devoted to the synthesis of the mot and che gene products. These estimates were also consistent with the hypothesis that the multiple polypeptides corresponding to cheA and cheM were the products of single genes.

The products of three chemotaxis-specific genes in Escherichia coli, cheM, cheD, and cheZ, are methylated. The cheZ gene codes for the synthesis of a 24,000 molecular weight polypeptide that appears in the cytoplasm. cheM codes for the synthesis of a membrane-bound polypeptide with a molecular weight of 61,000. cheD codes for another membrane-bound polypeptide with an apparent molecular weight of 64,000. CheM- mutants show chemotaxis toward some attractants (Tar- phenotype), while CheD- mutants respond to other attractants (Tsr- phenotype). The double mutant (CheD-, CheM-) does not respond to any attractant or repellent tested. Therefore, these polypeptides play a central role in chemotaxis. They collect information from two subsets of chemoreceptors and act as the last step in the chemoreceptor pathway and the first step in the general processing of signals for transmission to the flagellar rotor. It is suggested that they may be involved in both an initial process that reflects the instantaneous state of the chemoreceptors and in an integrative, adaptive process. Two other genes, cheX and cheW, are required for the methylation of the cheD and cheM gene products.

Chemoattractants and Chemorepellents

float

Chemoattractants

Bob Mesibov conducted attraction tests on E. coli against 53 amino acids and related chemicals. This was done by using mutants that reacted indifferently in L-serine and L-aspartate. Jerry Hazelbauer and Marge Dahl also tested the attraction of E. coli against the 85 common sugars and related chemicals. Among the highest attraction that were tested in this category were: D-galactose, D-glucose, D-mannitol, D-ribose, D-sorbitol, maltose and trehalose. A study later conducted by Wolfgang Epstein and Julius Adler revealed that phosphorotransferase sugars were also attractants. Some inorganic salts were also found to be attractants. (Adler 2011)

The study of leukocyte migration continues to provide new insights into the regulation of lymphocyte priming in secondary lymphoid organs and effector responses in inflamed tissues. Chemoattractant receptors have always been viewed as facilitators of cell movement into a tissue. This whole concept must now be revised with the discovery of sphingosine 1 phosphate receptors, which control cell exit from lymphoid tissues. The chemoattractants that regulate lymphoid tissue homing are usually different to those that regulate leukocyte recruitment to inflamed tissues. There is evidence, however, of inflammatory pathways of leukocyte recruitment in lymph nodes and, conversely of constitutive pathways in peripheral tissues. Finally, antagonists (or agonists) of chemoattractant receptors and their signalling pathways represent the most attractive strategy for the treatment of a wide range of inflammatory diseases, including allergy.

Chemorepellents

Testing for chemorepellents was done in a similar manner as the testing for chemoattractants. For E. coli, 164 different chemicals were tested by Wung-Wai Tao. The results of these tests showed that the most effective repellents were: short-chain fatty acids, hydrophobic amino acids, benzoate, indole, skatol, salicylate, and the ions Co²⁺, Ni²⁺, H⁺, and OH^-. (Adler 2011)

Although Paramecium has been widely used as a model sensory cell to study the cellular responses to thermal, mechanical and chemoattractant stimuli, little is known about their responses to chemorepellents. A convenient capillary tube repellent bioassay to describe 4 different compounds that are chemorepellents for Paramecium and compared their response with those of Tetrahymena. The classical Paramecium t-maze chemokinesis test was also used to verify that this is a reliable chemorepellent assay. The first two compounds, GTP and the oxidant NBT, are known to be depolarizing chemorepellents in Paramecium, but this is the first report of them as repellents in Tetrahymena. The second two compounds, the secretagogue alcian blue and the dye cibacron blue, have not previously been described as chemorepellents in either of these ciliates. Two other compounds, the secretagogue AED and the oxidant cytochrome c, were found to be repellents to Paramecium but not to Tetrahymena. The repellent nature of each of these compounds is not related to toxicity. The reason is because cells are completely viable in all of them. More importantly, all of these repellents are effective at micromolar to nanomolar concentrations, providing an opportunity to use them as excitatory ligands in future works concerning their membrane receptors and possible receptor operated ion channels.

Two Component System

The two component system is constituted of che proteins that are not involved in chemotaxis. Rather these che genes are more related to the transcriptional regulator in the cell. An important phenomenon occurs in the two component system that affects the rotation and movement of the flagella of bacteria. As the histidine residue of the first component is phosphorylated with ATP, the phosphate is transferred to the aspartate residue of the second component, which affects the rotation and movement of the flagella. Phosphorylation in the two component system also controls the genes that is needed for protein synthesis. The two component system is mainly found in bacteria, archaea, and single-celled eukaryotes. Repellants bring about the phosphorylation of cheA and cheY. Consequentially, this leads to the tumbling of bacteria's flagella. This enables the bacteria to move away from the repellant. Attractants block the phosphorlyation of cheA and cheY, therefore, tumbling is stopped. On the other hand, this enables the bacteria to go running towards the attractant. The bacteria's interactions with the repellant and attractant are called excitations. Excitations determine the movement of the bacteria. Adaption, the process following excitation, determines the bacteria's rotation. Repellants cause demethylation of the methylated MCP (methyl-accepting-chemotaxis-protein), while the attractant causes its methylation. Generally, repellants cause bacteria to rotate in a clockwise fashion and attractants cause bacteria to rotate in a counter-clockwise fashion. http://www.pnas.org/content/94/14/7263/F1.expansion.html (Adler 2011)

Responses of other Stimuli

Understanding that the environment is a major factor in deciding what a cell will do, there are other sensory stimuli besides chemicals. E. Coli were discovered to be repelled by blue light (phototaxis) which was determined by the fact that the chemoreceptors in E. Coli respond to light because most species of bacteria were former photosynthetic. Using light to fix carbon, they generated behavioral signals which now allowed E. Coli to respond to light. (Adler 2011) (Berg 2011)

E. Coli had demonstrated some responses to heat. More tests were conducted to see the effects of chemotactic system for thermotaxis. If E. Coli was missing 3 of the chemo proteins (cheY|W|A) then they would not react to the change in temperature, but rather the chemoreceptors (Tsr,Tar,Trg,Tap) all demonstrated some hand in bacterial thermotaxis. Falling in two categories, the cold receptor is Tap, while Tsr, Tar, Trg showed an increase of tumbling when there was a decrease of temperature vice versa the cold receptor would produce an inverted response. Receptors, if near their attracts, will demonstrate a different behavior after being methylated. If there is Serin, there will be no response due to Tsr. Some explanation that maybe offered to understand why the E. Coli “swim” is due to the hot temperatures that will cause denaturation making it more fluid. (Adler 2011) (Jeffory,Salman,Libchaber 2011)

Osmolarity plays a major role in where E. Coli are repelled by both high & low osmolarity but seek optimum osmolarity. This osmotaxis is highly dependent on the environment of E. Coli and the changes have different effects. If there is a rapid flow of water from the cell, it will be turgor, causing a process to try to restore the original conditions. The amount and concentration of the cytoplasmic water are controllers of the growth and the lower/higher the osmolarity, the less it will move versus optimum states of osmolarity. (Adler 2011)

Electrophysiology

If there are different responses to the environment, electrical properties must also play a role in E. Coli. Although experiments have played with the action potential of E. Coli there has yet to be any evidence. There proves to be electrical changes within E. Coli, but none that will come close to action potentials. The size of E. Coli also proves to be a difficulty because of its extremely small scale. If we were to measure the volts, it would degrade the cell wall and disrupt the cells function. To measure them, as of now, scientists monitor the blinking behaviors of E. Coli strains and determine their functions. (Adler 2011) (McDonald 2011)

Electrophysiology is the fastest growing of all the cardiovascular disciplines. Electrophysiologists are cardiologists who have additional education and training in the diagnosis and treatment of abnormal heart rhythms. Close collaboration between electrophysiologists and other doctors who treat patients with heart disease is very important.

An electrophysiology study (EPS) is a test that can help predict if an individual is at high risk for sudden cardiac arrest. Signals are administered to the heart muscle in patterns to see if they will stimulate ventricular tachycardia (VT). The test is performed in a safe and controlled electrophysiology laboratory at a hospital or clinic and the patient is in no danger. In an EP study, local anesthetics are used to numb areas in the groin or near the neck, and small catheters are passed into the heart to record its electrical signals. During the study, the physician studies the speed and flow of electrical signals through the heart, identifies rhythm problems and pinpoints areas in the heart's muscle that give rise to abnormal electrical signals. Anyway, electrophysiology (EP) is an emerging healthcare science and therapy. EP is a subspecialty of cardiology that focuses on diagnosing and treating cardiac arrhythmias. The cardiac electrophysiology technologist may come from a variety of allied health professionals (RT, RN, CVT, EMT, RRT and PA), assists an EP cardiologist during diagnostic and invasive procedures including programmed electrical stimulation, sterile scrub technique, electro-anatomical 3D mapping, catheter ablation for cardiac arrhythmias and device implantation for cardiac rhythm management such as pacemakers and other advanced implantable devices.

An electrophysiology study can: 1) Identify which patients who have had a prior heart attack, or MI, are at risk for serious ventricular arrhythmias and, perhaps, SCA. 2)Assist in determining which patients may require aggressive treatment to prevent sudden cardiac arrest. 3) Identify individuals whose hearts cannot be induced into dangerous arrhythmias. They appear at lower risk for developing spontaneous, sustained VT that can lead to ventricular fibrillation and sudden cardiac arrest.

We may need an EP study: 1)To determine the cause of an abnormal heart rhythm. 2)To locate the site of origin of an abnormal heart rhythm. 3)To decide the best treatment for an abnormal heart rhythm.

References

Adler, Julius (2011). "My Life with Nature". The Annual Review of Biochemistry. Retrieved 2011-10-27.

Berg, Howard (2004). "E Coli in Motion". Biological and Medical Physics Biomedical Engineering. Retrieved 2011-10-29.

Jeffory,Salman,Libchaber, Marie,Hanna,Albert (2004/05). "Thermotaxis in E. Coli" (PDF). The Rockefeller University. Retrieved 2011-10-29. {{cite web}}: Check date values in: |date= (help)CS1 maint: multiple names: authors list (link)

McDonald, Casey (2011). "E. coli Voltmeters". Biotechniques. Retrieved 2011-10-29.
Foster, John W., Slonczewski, Joan L.. Microbiology. 1st ed. New York. 2009.

Biochemistry in Medicine

Carbon monoxide (CO) is a colorless and ordorless gas. CO has a greater affinity for hemoglobin than oxygen and when it binds to hemoglobin it is called a carboxyhemoglobin, COHb. This can be fatal because not only does it lessen the amount of protein able to bind to oxygen, but it increases the affinity for oxygen dramatically. This is not necessarily good because even though it binds well with oxygen now, it will less likely want to release the oxygen into the tissue because it wants to be bound to the oxygen more. Therefore very little oxygen will be released into the tissue after it binds to the lungs. This leads to oxygen deprivation in the tissue that can become severe rapidly. This will eventually lead to the person’s death because of respiratory failure. In general death will occur if COHb levels are above 60%. To protect oneself from accidental exposure to high levels of carbon monoxide in the house, install a simple CO detector.

The effects of COHb (Carboxyhemoglobin

1) If COHb levels are below 10% no effect
2) If COHb levels are at 15% the person may experience headaches
3) If COHb levels are between 20%-30% the headache is severe and the person may experience nausea, dizziness, confusion, disorientation, and visual disturbances
4) If COHb levels are between 30%-50% the neurological symptoms become more severe
5) If COHb nears 50% the person will lose consciousness and sink into coma and respiratory failure may follow.

Sources of Carbon Monoxide

1) Engines
2) Household Furnace
3) Tobacco smoke
4) Byproducts of natural processes

Reference

1. Nelson, David L., Michael M. Cox, and Albert L. Lehninger. "Carbon Monoxide: A Stealthy Killer." Lehninger: Principles of Biochemistry. New York: W. H. Freeman and, 2005. N. pag. Print. Polar lipids of membranes consistently undergo metabolic turnover. The rate of the synthesis is equal to the rate of the breakdown. The breakdown is generally promotedy by hydrolytic enzymes in lysosoms. However, a serious disese can occur if there is an accumulation of the partial breakdown products in the tissue caused by a dfect in the enzymes that is responsible for sphingolipid degradation.

An example of this is the Niemann-Pick disease that is caused by a genetic defect in sphingomyelinase, an enzyme that cleaves phosphocholine from sphingomyelin. Sphingomyelin is found in the brain, spleen, and liver. The disease causes infants to have mental retardation and may result in an early death. Another example is the Tay-Sachs disease, where the body has a lack of enzyme hexosaminidase. The lack of the enzyme causes the build up of ganglioside GM2, which ultimately leads to the Tay-sachs disease. The symptoms of this disease includes progressive retardation in development, paralysis, lindness, and death in three or four years.

A way to detect these diseases is by testing prospective parents and then testing their DNA to determine the exact nature of the defect and the probability it would be passed on to the offspring. If the female is pregnant then doctors would test the cells inside the placenta or the fluid surrounding the baby.

Reference

1. Nelson, David L., Michael M. Cox, and Albert L. Lehninger. "Inherited Human Diseases Resulting from Abnormal Accumulations of Membrane Lipids." Lehninger: Principles of Biochemistry. New York: W. H. Freeman and, 2005. N. pag. Print. Scurvy is a disease that causes degeneration of connective tissue. It is caused if there is a deficient amount of Vitamin C found in the body. Scurvy if left untreated can cause small hemorrhages, tooth loss, poor wound healing, the reopening of old wounds, bone pain and degeneration and heart failure. To regain the deficient vitamin C level one must eat fruits and vegetables.

How consuming vitamin C combats Scurvy

Collagen is in the repeated tripeptide unit Gly-X-Y where X and Y are generally Pro or 4-Hyp. It is necessary that the Pro residue in the Y position to be in the Carbon-gamma exo conformation and requires the Pro residue in the X position to have the Carbon-gamma endo conformation. The 4-Hyp if introduced can destabilize the helix. When vitamin C is absent t leads to collagen instability because the molecule can not hydroxylate the Pro at the Y position. A special enzyme is required to hydroxylate the Pro residue in procollagen, the enzyme is called prolyl 4-hydroxylase. Prolyl 4-hydroxylase is a alpha2Beta2 tetramer in all vertebrate. The alpha subunit was found to be the site of proline-hydroxylating activity. Vitamin C is essential in hydroxylating the proline to stabilize the collagen. Vitamin C is found in high abundance in fruits and veggies, particularly in lemons.

Reference

1. Nelson, David L., Michael M. Cox, and Albert L. Lehninger. "Why Sailors, Exploeres, and College Students Should Eat Their Fresh Fruits and Vegetables." Lehninger: Principles of Biochemistry. New York: W. H. Freeman and, 2005. N. pag. Print. X-ray crystallography is a technique used by biochemist to determine the three dimensional structure of an enzyme, protein, molecule, etc. Although the technique requires the molecule to be able to be crystallized it has helped scientist discover how drugs can prevent certain enzyme from reacting. By determining the three dimensional structure of the protein or enzyme scientists can determine how enzyme folds and binds. From that information, scientists can design certain drugs that only stop that enzyme. For example, scientists used x-ray crystallography to determine the structure of the COX enzyme that is responsible for arthritis. Now that the scientists know the three dimensional structure of the COX enzyme, they can create drugs that would be able to stop it, such as aspirin. Therefore X-ray crystallography is a powerful tool that biochemist and scientists can use to discover new drugs that can prevent certain enzymes from activating.

Reference

1. Medicine by Designs NIH Publication No. 06-474 Reprinted July 2006 http://www.nigms.nih.gov By understanding how antibodies work scientists have developed ways to prevent the spread of cancer cells. Two therapeutic monoclonal antibody have been developed that has aided in the fight against cancer.
1. Rituxan

Rituxan was the first therapeutic monoclonal antibody that targets tumor cells passed by the FDA. It targets the tumor fingerprint on the surface of immune cells known as B cells in non-Hodgkin’s lymphoma.

2. Herceptin

Heceptin is the other therapeutic monoclonal antibody that targets breast cancer cells. How it works is that it binds to the cell receptors of the breast cancer and acts as a signal to lure immune cells to kill the cancer cell. This function helps prevent breast cancer from spreading to other organs.

Reference

1. Medicine by Designs NIH Publication No. 06-474 Reprinted July 2006 http://www.nigms.nih.gov

Biochemical Role in Neuropsychiatric Disease

A proposed chart describing the development of schizophrenia.

Schizophrenia is a severe neuro-psychiatric disease that affects approximately 1% of the world's population. It is characterized by a variety of symptoms that include hallucinations and delusions, and has five sub-categories for diagnosis: catatonic, residual, disorganized, undifferentiated and paranoid. The exact underlying biochemical mechanism of how schizophrenia is developed can be attributed to a multitude of factors, some of which are genetics, early environment, neurobiology and psychological and social processes.

Albeit much research has been done in neurobiology and other fields, researchers have not yet isolated a single organic cause. Due to the multitude of factors that play a role in this disease, research can be approached in a variety of methods.

Symptoms

The symptoms of schizophrenia can be characterized by three symptom clusters: positive, negative and cognitive. The positive symptoms include any type of delusion or hallucination. Negative symptoms are a deficit of normal emotional responses. Oftentimes people experiencing negative symptoms can feel depressed and unmotivated. Lastly, cognitive symptoms refer to problems in attention, thought, perception, learning and memory.

Genetic Correlations with Schizophrenia

The most prominent causes of schizophrenia lies in genetics factors. People who have a family who have experienced psychosis or schizophrenia have a 5-10% chance of developing it themselves.

A number of genes have been shown to have correlation with those experiencing schizophrenia. One particular type of genetic mutation, copy number variation (CNV), have been seen in higher frequencies for those affected than in control groups. These genomic hot spots may one day be the key for treatments.

More recently, de novo mutations have also been regarded as a key component for the cause of schizophrenia.

Mechanism

The Dopamine Hypothesis of Schizophrenia The Dopamine Hypothesis of Schizophrenia is a model used by scientists to explain many of schizophrenic symptoms. The model claims that a high fluctuation of levels of dopamine may be responsible for hallucinations and delusions brought on by schizophrenics. This model has helped progress the development of antipsychotics, which are drugs that stabilize positive symptoms by acting as a dopamine-receptor antagonist.

Psychological Psychological factors may come into play and cause schizophrenia is an individual is under stress of confusing situations. Although much research has been done on whether childhood played a significant role, not much has been found.

Treatment

There has been a variety of antipsychotic drugs that are available for schizophrenics to take. These drugs work by blocking the dopamine receptors, thus curing the patient from many positive symptoms. However, not many drugs are available for negative or cognitive symptoms.

Future Treatment

With the advancement of whole genome sequencing as well as personalized medicine, it may be possible to better treat schizophrenics. With genes associated with schizophrenia, such as VIPR2, being discovered, scientists and doctors together may develop novel medicines to suppress excess hormones or other proteins.

It has been recorded that over a quarter of homeless people in the United States are schizophrenics. Although many have been diagnosed and put on medication, few stick to the treatment, resulting in a poor prognosis. Many schizophrenics have reported that antipsychotic drugs disable their normal day-to-day function. For this reason, many stop taking their medication. With personalized medicine, however, this may change. If each patient can be have a medicine tailored to their genome, resulting in minimal side effects, schizophrenics could return to a "normal" lifestyle.

Sources

"Schizophrenia" Concise Medical Dictionary. Oxford University Press, 2010. Oxford Reference Online. Maastricht University Library. 29 June 2010 prepaid subscription only Bell V, Halligan PW, Ellis HD. Explaining delusions: a cognitive perspective. Trends in Cognitive Science. 2006;10(5):219–26. doi:10.1016/j.tics.2006.03.004. PMID 16600666. Warner R. Recovery from schizophrenia and the recovery model. Curr Opin Psychiatry. 2009;22(4):374–80. doi:10.1097/YCO.0b013e32832c920b. PMID 19417668 Burns J. Dispelling a myth: developing world poverty, inequality, violence and social fragmentation are not good for outcome in schizophrenia. Afr J Psychiatry (Johannesbg). 2009;12(3):200–5. PMID 19894340.

Overview

Autism is a disorder to the brain that makes it difficult for the individual to communicate and relate with others. The reason for this is because different areas of the brain are not able to work together.

Symptoms

Symptoms of autism are usually displayed before the age of 3 and last throughout the life of the individual. Below is a list of symptoms:

-difficulty with communication verbally thus giving the individual the inability to participate in a conversation

-difficult with non-verbal communication such as recognizing expressions and movements

-difficulty with social interactions thus giving the individual the inability to make friends

-lack of imagination

-difficulty adjusting to new things such as changes in routine or environment

-repetitive body movement such as flapping ones hand

-preoccupation with unusual objects

Causes

Though the cause of autism cannot be pinpointed to a specific source, two major sources have been identified as probable causes: genetics and environment.

In regards to genetics, studies have yet to prove that a gene is the single cause of this disease. However, mutations such as single base changes or have shown that autism can result from genetics and also implicate that it can be hereditary. An individual with autism is six times more likely to have a functional variant in genes expressed in the brain.

The environment also can affect the genetics resulting in de novo mutations, mutations that occur for the first time in a family member as a result of a mutation in either a sperm or egg cell. Research has shown that older men who decide to have children would most likely have a child with autism since sperm cells are at greater risks of mutations for older men. A correlation between paternally inherited DNA and paternal age shows that boys with autism were six times more likely to have a father in his 40s.

References

Insel, Thomas. "The New Genetics of Autism – Why Environment Matters." National Institute of Mental Health. N.p., 4 Apr. 2012. Web. 6 Dec. 2012. <http://www.nimh.nih.gov/about/director/2012/the-new-genetics-of-autism-why-environment-matters.shtml>.

"Autism - Topic Overview." WebMD. Healthwise, 10 Apr. 2010. Web. 6 Dec. 2012. <http://www.webmd.com/brain/autism/autism-topic-overview>. Structural Biochemistry/Bipolar

Overview

Huntington's disease is an autosomal dominantly inherited disease characterized by slowly progressive neurodegeneration associate with abnormal and involuntary movements. It also affects muscle coordination and ultimately leads to cognitive decline and psychiatric problems. This disease tend to be more common in Western European people than Asian or African people. Any child of an affected person has a 50% change of inheriting the disease.

File:Huntington brain.jpeg

A brain affected by Huntington's disease compared to a healthy brain

Cause

Huntington's disease occurs when there is a mutation leading to unnecessary repeats of three nucleotides, also called trinucleotide repeats. The trinucleotide is the sequence CAG, and is caused by a specific genetic defect on chromosome 4. The trinucleotide sequence repeats many more times than necessary, ranging from 36-120 times. A normal individual unaffected by the disease only has repeats the trinucleotide 10-28 times. The accumulation of the trinucleotide repeats cause Huntington's because the polyglutamine stretches become increasingly prone to aggregation as their lengths increase.

Genetics

All humans have two copies of the Huntingtin gene (HTT or HD). This gene codes for the protein Huntingtin (Htt). Huntington's Disease is caused by the expansion of a CAG trinucleotide repeat in the first exon of the HTT. The HTT is composed of 67 exons and generates two mRNAs that differ in the length of their 3' untranslated regions. When the length of this repeated section reaches a certain point, it produces an altered from of the protein called mutant Hungtingtin protein (mHtt). When an individual inherits one copy of the gene with an expanded trinucleotide repeat from an affected parent, he or she will also be affected by the Huntington's Disease. Each offspring has a 50% change of inheriting the mutant allele. In some cases when both parents have the mutant gene, the possibility increases to 75%. When one parent had bas both the mutant gene, there is a 100% chance of the offspring to inherit the mHtt.

There are two forms of Huntington's disease:

Adult-onset Huntington’s disease(most common), individuals with this form usually develop symptoms in their mid 30s to 40s

Early-onset: form of Huntington disease where symptoms begin in childhood or adolescence – it is found that there are only a small number of cases of this form.

Mechanism

The Htt gene is expressed in all mammalian cells especially in the brain and testes. The function of Htt in humans is unclear. the Htt interacts with proteins that are involves in transcription, cell signaling and intracellular transporting. In animals, Htt is importnat for embryonic development. Without the Htt, embryos tend to die.. Htt also acts as an anti apoptotic agent and prevents cell death. In addition, there are cellular changes through which the toxic function of mHtt produces the Huntington's Disease pathology. During the modification of mHtt, cleavage of the protein can leave shorter fragments of the polyglutamine expansion. Because glutamine is polar, it causes interactions with other proteins when overabundant in Htt proteins. therefore, the mHtt molecules form hydrogen bonds with each other, resulting in a aggregate protein.

Symptoms

Behavioral changes may occur, usually before movement problems. These include behavioral disturbances, irritability, hallucinations, moodiness, restlessness or fidgeting, psychosis and or paranoia.

Abnormal and unusual movements such as: facial movements (i.e. grimaces), head turning to shift eye position, sudden jerking movement of limbs, face and other body parts, slow, uncontrolled movements, and or unsteady gait.

Those affected by Huntington's disease may also develop dementia. Once symptoms of dementia develops it will slowly get worse and an individual will gain disorientation or confusion, loss of judgement, loss of memory, personality changes and speech changes.

Additional symptoms may also occur that may be associated with Huntington's such as: anxiety, stress, tension, difficultly swallowing and speech impairment.

Other symptoms may occur more frequently in children such as rigidity, slow movements, and tremors.

Diagnosis

Genetic testing can be used to confirm a physical diagnosis if there is no family history of Huntington's Disease. The genetic test can confirm if an individual or embryo carriesan extended copy of the trinucleotide repeat in the HTT gene. Because Huntington's Disease is an autosomal dominantly inherited disease, medical professionalists strongly recommend individuals who are at risk to seek a diagnosis. The genetic test consists of a blood test which counts the number of CAG repears. Excessive unintentional movemnts in any part of the body are often why people seek medical consultation. Cognitive and psychiatric symptoms are rarely the first diagnosed. they are usually only recognized when the disease develops further. CT and MRI can show the atrophy of caudate nuclei in the disease. A pre-symptomatic test can be a very personal decision. Over 95% of individuals at irisk of inheriting Huntington's Disease do not test because there is no treatment for this disease. Some take the test because of the anxiety of not knowing, but the risk of suicide is procen to be higher after a positive test result. Some who found out that they have not inherited the disorder experience survivor guilt regards to family members who are affected.

Management

Currently, there is no cure for Huntington's Disease. There are treatments to reduce the severity of the symptoms. As the disease progress, the ability to care for oneself declines and a caregiver becomes necessary. There has been some usefulness in physical, occupational, and speech therapy. The involuntary movements, or chorea, is treated by tetrabenazine. Although it helps reduce chorea, many drugs are still under investigation. Psychiatric symproms are treated with medications that are used in the general population. Depression medications and long term neuropsychiatric treatments are combined to treat these symptoms. Life expectancy in Huntington's Disease is about twenty years after the visible symptoms. Most life-threatening complications come from muscle coordination and decline in cognitive function. Pneumonia, heart disease and suicide are some big causes of death in those with the disorder.

References

1. http://themedicalbiochemistrypage.org/huntingtondisease.php
2. PubMed Health: Huntington's disease. 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001775/>
3. http://commons.wikimedia.org/wiki/File:Huntington_brain.jpeg
4. Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert. Biochemistry. 7th ed. W.H. Freeman and Company: New York, 2012.