Within the cell nucleus, DNA methyltransferase (DNMT) enzymes convert cytosine to 5-methylcytosine using S-adenosylmethionine (SAM) as the methyl donor. The TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine. Because the TET proteins are α-ketoglutarate-dependent enzymes, their activity is inhibited by 2-hydroxyglutarate, a metabolite produced in excess specifically in cells with mutated isocitrate dehydrogenase 1 or 2 (IDH1/2) proteins. While both IDH1 and IDH2 are found within the cytoplasm, IDH2 is also located in cellular mitochondria.