Clinical Connections Mutations in Citric Acid Cycle Enzymes Possibly because the

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Clinical Connections Mutations in Citric Acid Cycle Enzymes Possibly because the citric acid cycle is a central metabolic path- Defects in isocitrate dehydrogenase also promote cancer in an way, severe defects in any of its components are expected to be indirect fashion. Many cancerous cells exhibit a mutation in one of incompatible with life. However, researchers have documented the two genes for the enzyme, suggesting that the unaltered copy is mutations in the genes for several of the cycle's enzymes, includ- necessary for maintaining the normal activity of the citric acid ing a-ketoglutarate dehydrogenase, succinyl-CoA synthetase, and cycle, while the mutated copy plays a role in carcinogenesis. succinatc dehydrogenase. These defects, which are all rare, Interestingly, the mutation usually converts an active-site Arg typically affect the central nervous system, causing symptoms residue to His, indicating some strong selective pressure for a such as movement disorders and neurodegeneration. A rare form gain- of-function mutation (most mutations in proteins lead to loss of fumarase deficiency results in brain malformation and devel- of function). The mutated isocitrate dehydrogenase no longer opmental disabilities. Individuals who have a different fumarase carries out the usual reaction (converting isocitrate to a- defect show a higher risk of developing leiomyomas, noncancer- ketoglutarate) but instead converts a-ketoglutarate to 2- ous tumors such as uterine fibroids. A small percentage of these do hydroxyglutarate in an NADPH-dependent manner. The become malignant. The other citric acid cycle enzyme mutations mechanism whereby 2-hydroxy-glutarate contributes to are also associated with cancer. One possible explanation is that a carcinogenesis is not clear, but its involvement is bolstered by the defective enzyme contributes to carcinogenesis (the development observation that individuals who harbor other mutations that lead of cancer, or uncontrolled cell growth) by directly interfering with to 2-hydroxyglutarate accumulation have an increased risk of the cell's vital pathways for energy metabolism. Another developing brain tumors. possibility is that a defective enzyme causes the accumulation of particular metabolites, which are responsible for altering the cell's developmental face Fumarase appears to be linked to cancer through the second mechanism. Normal cells respond to a drop in oxygen avail- ability (hypoxia) by activating transcription factors known as hypoxia-inducible factors (HIFs). These proteins interact with DNA to turnm on the expression of genes for glycolytic enzymes and a growth factor chat promotes the development of new blood vessels. When the fumarase gene is defective, fumarate accumulates and inhibits a protein that destabilizes HIFs. As a result, the fumarase deficiency promotes glycolysis (an anacrobic pathway) and the growth of blood vessels. These two adaptations would favor tumors, whose growth, although characteristically rapid, may be limited by the availability of oxygen and other nutrients delivered by the bloodstream.

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The biochemical pathways play a crucial role in maintaining the normal physiological function of the body. The citric acid cycle is one of such cycles which regulates the function of the body. This cycle contains various enzymes and defect in even a single enzyme can be very detrimental to health, leading to disorders related to central nervous system and carcinogenesis.

Studies have shown that defective fumarase enzyme promotes carcinogenesis in humans due to lack of body's capability to cope up with hypoxia secondary to stabilization of HIF. This causes generation of more amount of microvessels and make the surrounding tissue nutrient deficient thus promoting carcinogenesis. Similarly, the role of defective enzyme isocitrase dehydrogenase has been also shown to be associated with pathologies. This defective enzyme shows a gain-of-function mutation due to change in a single amino acid in its active site thus leading to change in its normal biological function. Thus, the enzyme is no longer capable of conducting normal function and hence accumulates a secondary product which is shown to be responsible for brain cancers.

Thus, this explains that alteration in normal biochemical pathways can be very deleterious for the body and can lead to life-threatening conditions such as cancer.

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