Structural Biochemistry/Proteases


Proteases are a protein-digestive enzyme that cleaves protein through hydrolysis, the addition of water to the peptide bond. Although hydrolysis of the peptide bond is thermodynamically favored, it is still a slow reaction without the enzyme. This is due to the fact that the peptide bond is very stable due to its resonance structure forming a partial double bond. The specificity of the peptide bond they hydrolyze is high.

A number of proteolytic enzymes participate in the breakdown of proteins in the digestive systems of mammals and other organisms. An example of a protein-digesting enzyme may be seen in the protease called pepsin.[1] Pepsin is one of two components of gastric juice.[1] Pepsin works by attacking the exposed peptide bonds.[1] Unlike most enzymes which can be denatured when exposed to extreme pH, pepsin works at its optimal performance in a highly acidic environment.[1]

The 4 main class of proteases are: Serine Proteases, Cysteine Proteases, Aspartyl Proteases, and Metalloproteases.


Serine Proteases use serine residue to create a nucleophilic amino acid that cleaves the peptide bond. They are responsible for various functions such as blood clotting, and digestion One such enzyme, known as Chymotrypsin, cleaves peptide bonds selectively on the carboxyl terminal side of the large hydrophobic amino acids such as tryptophan, tyrosine, phenylalanine, and methionine. Chymotrypsin is a good example of the use of covalent catalysis.


Cysteine, Aspartyl, MetalloproteasesEdit

Not all proteases utilize strategies based on activated serine residues. Classes of proteins have been discovered that employ three other approaches to peptide-bond hydrolsis:

1. Cysteine Proteases 2. Aspartyl Proteases 3. Metalloproteases

In each case, the strategy is to generate a nucleophile that attacks the peptide carbonyl group.

An example of a Cysteine Protease is papain, which is found in the papaya fruit. The catalytic mechanism that this enzyme uses to hydrolyze a peptide bond involves the activation of a cysteine residue by a histidine residue, both present in the active site. The result of this activation is a powerful nucleophile that is able to attack the carbon present in the carbonyl group present next to the peptide bond.


Aspartyl proteases are a type of proteolytic enzymes classified under endonucleases. Aspartyl proteases are known to exist in vertebrates, plants, plant viruses, as well as in retroviruses. Aspartyl proteases is characterized by having a frequent sequence of Asp- Thr- Gly amino acid triad. Most aspartate proteases are found as monomeric enzymes consisting of two domains. Aspartyl proteases are important for the human body in regulating blood pressure, health, and digestion.


An example of Metalloprotease would be Zinc Metalloproteases which include the digestive enzymes carboxypeptidases, various matrix metalloproteases (MMPs) that are secreted by cells, and one lysosomal protease. MMP's have the role of degrading extracellular matrix during tissue remodeling, cell signaling the release of cytokines or growth factors through cleavage of proteins.

Protease InhibitorsEdit

Several important drugs are Protease Inhibitors. HIV protease is a type of aspartyl protease that can be inhibited.


Berg, Jeremy Mark., John L. Tymoczko, and Lubert Stryer. "Chapter 9." Biochemistry. Basingstoke: Palgrave Macmillan, 2012. 263-71. Print.

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