Biochemistry/Metabolism

What is life? What makes life work? Life is not static; it is defined by activity. A cell has to perform certain tasks to stay alive. This activity has to be powered by fuel; the fuel is converted into energy, to keep the cell running, building blocks for new biomolecules, and waste products. This process is called metabolism.

ATP as an intermediate energy carrier

We have already seen how ATP is a universal "energy currency" in the cell, and how its high-energy phosphate can store and release this energy efficiently. But ATP is only a short-term energy storage; a hard-working human can use up to one pound of ATP per minute. How can that be?

The answer lies in the medium- and long-term energy storage molecules, notably phosphoenol pyruvate (PEP), acetyl phosphate, and creatine phosphate. Each of these molecules carries a phosphate group with an ever higher transfer potential than that of ATP. ATP is continuously regenerated by transferring phosphate groups from these molecules to ADP. For example, the reaction of creatine phosphate is

Creatine phosphate + ADP + H⁺ ⇋ ATP + creatine

a reaction which is catalyzed by the creatine kinase, and highly in favor of the "ATP side" of the equation.

Electron carriers

Most of the energy of eucaryotic lifeforms derives from oxidating fuel molecules, that is, the transfer of electrons from fuel molecules to oxygen. The fuel molecules are oxidized, while the oxygen is reduced. A rather radical form of oxidation is fire, which oxidizes its fuel directly with oxygen. As spontaneous combustion one ones cells is rather unpleasant, the electrons are carried through several steps from the fuel molecules to the final electron acceptor, oxygen. The flow of electrons causes a proton gradient in the mitochondrial membranes, which in turn is used by the enzyme ATPase (or proton pump) to generate ATP. This process, utilizing anelectron transport chain, is called oxidative phosphorylation.

The electron carrier molecules of choice are NADH and FADH₂. They are pyridine nucleotides (also called flavions).

	Reduced form	Oxidized form
NADH	NADH	NAD⁺
FADH₂	FADH₂	FAD

Both molecules are also for biosyntheses that require reducing power. Especially a variant of NADH, NADPH, is used for this purpose.

With all these high-energy bonds and electron-carrying molecules around, one would expect to see wild, uncontrolled chemical reactions occurring in the cell. However, the opposite is the case: Without a catalyst, ATP is quite slow to hydrolize and give its phosphate group to water. Also, all three electron-carrying molecules, NADH, NADPH, and FADH₂, are slow to react with O₂ without a catalyst.

Cancer Cell Metabolism

Glutamine addiction: a new therapeutic target in cancer

The Warburg observation that cancer cells use up an unusually high level of glucose and produce more lactic acid has been around since the 1920’s. It wasn’t noted till 1955 by Eagle, that cancer cells also use up a high level of the amino acid glutamine. In the article, Glutamine addiction: a new therapeutic target in cancer, Wise and Thompson highlight the role glutamine plays in cancer cell growth, protein translation, anaplerosis, and macromolecular synthesis.

Glutamine is the chief donor of nitrogen to cancer cells for the cells to multiply. When glutamine gives up its amide, it is converted into glutamic acid, which is the main nitrogen donor for nonessential amino acid synthesis. This amino acid biosynthesis makes glutamine a main ingredient for the cancer cells’ need for protein translation. Stemming off of biosynthesis is Myc, a basic protein that binds 11 of the genes involved in nucleotide biosynthesis. Myc activation is a commonly observed in cancer and is identified as the driving force behind the spread of lymphomas and small cell lung cancer. Myc facilitates glutamine consumption and supports the change of glutamine into glutamic acid, and finally into lactic acid. This satisfies the Warburg observation of the unusual lactic acid production of cancer cells.

The target of rapamycine (TOR) controls many cell functions such as cell growth, reproduction, motility, and protein synthesis. The “master regulator of protein translation, the mammalian target of rapamycin complex (TOR), is responsive to glutamine levels” (Wise and Thompson, 2010). This was initially discovered in yeast, where TOR activation was found to be dependent on glutamine levels.

The article also describes how glutamine adds to macromolecular (DNA, RNA, and proteins) synthesis by producing NADPH (nicotinamide adenide dinucleotide phosphate, a reducing agent in anabolic reactions) and providing the cancer cell with a substrate source which refills the mitochondrial carbon pool (anaplerosis). This refilling of the carbon pool is necessary for the synthesis of proteins, lipids, and nucleotides.

All of these facts relating glutamine importance to cancer cells may be a potential target in altering cancer cell metabolism. However, it is still unknown if this is a viable target for the treatment of cancer. Ideas include suppressing the glutamine uptake, TOR activation, or the anaplerosis of the cancer cells. Using an enzyme to lower blood glutamine levels is another possible method.

References

Wise & Thompson, Glutamine addiction: a new therapeutic target in cancer, 2010, Department of Cancer Biology, University of Pennsylvania, Elsevier Ltd.