Citric acid cycle/ja: Difference between revisions

In [[cancer]], there are substantial [[Warburg effect (oncology)|metabolic derangements]] that occur to ensure the proliferation of tumor cells, and consequently metabolites can accumulate which serve to facilitate [[tumorigenesis]], dubbed onco[[metabolites]]. Among the best characterized oncometabolites is [[2-hydroxyglutarate]] which is produced through a [[heterozygous]] [[gain-of-function mutation]] (specifically a [[Neomorphic mutation|neomorphic]] one) in [[isocitrate dehydrogenase]] (IDH) (which under normal circumstances catalyzes the [[oxidation]] of [[isocitrate]] to [[oxalosuccinate]], which then spontaneously [[Decarboxylation|decarboxylates]] to [[Alpha ketoglutarate|alpha-ketoglutarate]], as discussed above; in this case an additional [[Organic redox reaction|reduction]] step occurs after the formation of alpha-ketoglutarate via [[NADPH]] to yield 2-hydroxyglutarate), and hence IDH is considered an [[oncogene]]. Under physiological conditions, 2-hydroxyglutarate is a minor product of several metabolic pathways as an error but readily converted to alpha-ketoglutarate via hydroxyglutarate dehydrogenase enzymes ([[L2HGDH]] and [[D2HGDH]]) but does not have a known physiologic role in mammalian cells; of note, in cancer, 2-hydroxyglutarate is likely a terminal metabolite as isotope labelling experiments of colorectal cancer cell lines show that its conversion back to alpha-ketoglutarate is too low to measure. In cancer, 2-hydroxyglutarate serves as a [[Competitive inhibition|competitive inhibitor]] for a number of enzymes that facilitate reactions via alpha-ketoglutarate in alpha-ketoglutarate-dependent [[dioxygenase]]s. This mutation results in several important changes to the metabolism of the cell. For one thing, because there is an extra NADPH-catalyzed reduction, this can contribute to depletion of cellular stores of NADPH and also reduce levels of alpha-ketoglutarate available to the cell. In particular, the depletion of NADPH is problematic because NADPH is highly compartmentalized and cannot freely diffuse between the organelles in the cell. It is produced largely via the [[pentose phosphate pathway]] in the cytoplasm. The depletion of NADPH results in increased [[oxidative stress]] within the cell as it is a required cofactor in the production of [[Glutathione|GSH]], and this oxidative stress can result in DNA damage. There are also changes on the genetic and epigenetic level through the function of [[Histone code|histone lysine demethylases]] (KDMs) and [[Ten-Eleven Translocation 2|ten-eleven translocation]] (TET) enzymes; ordinarily TETs hydroxylate [[5-Methylcytosine|5-methylcytosines]] to prime them for demethylation. However, in the absence of alpha-ketoglutarate this cannot be done and there is hence hypermethylation of the cell's DNA, serving to promote [[Epithelial–mesenchymal transition|epithelial-mesenchymal transition (EMT)]] and inhibit cellular differentiation. A similar phenomenon is observed for the Jumonji C family of KDMs which require a hydroxylation to perform demethylation at the epsilon-amino methyl group.Additionally, the inability of prolyl hydroxylases to catalyze reactions results in stabilization of [[HIF1A|hypoxia-inducible factor alpha]], which is necessary to promote degradation of the latter (as under conditions of low oxygen there will not be adequate substrate for hydroxylation). This results in a [[Pseudohypoxia|pseudohypoxic]] phenotype in the cancer cell that promotes [[angiogenesis]], metabolic reprogramming, [[cell growth]], and [[Cell migration|migration]].