FIGURE 24-4 2-Hydroxyglutarate is a cancer-specific metabolite. Isocitrate dehydrogenase (IDH) is an enzyme in the TCA cycle. It converts isocitrate into α-ketoglutarate, which is then further converted into succinyl CoA. Some mutant forms of IDH found in many brain cancers create a novel metabolite, 2-hydroxyglutarate (2HG), from α-ketoglutarate. 2-Hydroxyglutarate accumulates to extremely high levels in these cells and inhibits the activity of proteins that require α-ketoglutarate for their function. Many of the enzymes that are inhibited control gene expression, such as the TET family of DNA hydroxylases, or the methylation state of histones, such as histone methyl transferases and demethylases.