In Desulfotalea psychrophila (DpIDH) and porcine (PcIDH) there are three substrates bound to the active site. Isocitrate binds within the active site to a conserved sequence of about eight amino acids through hydrogen bonds. These acids include (may vary in residue but with similar properties) tyrosine, serine, asparagine, arginine, arginine, arginine, tyrosine, and lysine. Their positions on the backbone vary but they are all within a close range (i.e. Arg131 DpIDH and Arg133 PcIDH, Tyr138 DpIDH and Tyr140 PcIDH). The metal ion (Mg2+, Mn2+) binds to three conserved amino acids through hydrogen bonds. These amino acids include three Aspartate residues. NAD+ and NADP+ bind within the active site within four regions with similar properties amongst IDH enzymes. These regions vary but are around [250–260], [280–290], [300–330], and [365–380]. Again regions vary but the proximity of regions are conserved. Clinical significance Specific mutations in the isocitrate dehydrogenase gene IDH1 have been found in several tumor types. Notably brain tumors including astrocytoma, oligodendroglioma and glioblastoma multiforme, with mutations found in nearly all cases of secondary glioblastomas, which develop from lower-grade gliomas, but rarely in primary high-grade glioblastoma multiforme. Patients whose tumor had an IDH1 mutation had longer survival. Furthermore, mutations of IDH2 and IDH1 were found in up to 20% of cytogenetically normal acute myeloid leukemia (AML). These mutations are known to produce (D)-2-hydroxyglutarate from alpha-ketoglutarate. (D)-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate. This leads to a hypermethylated state of DNA and histones, which results in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. Ultimately, this may lead to the types of cancer described above. Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome. However, recent studies have also shown that (D)-2-hydroxyglutarate may be converted back into alpha-ketoglutarate either enzymatically or non-enzymatically. Further studies are required to fully understand the roles of IDH1 mutation (and (D)-2-hydroxyglutarate) in cancer. Recent research highlighted cancer-causing mutations in isocitrate dehydrogenase which may cause accumulation of the metabolite D-2-hydroxyglutarate (D-2HG). Notarangelo et al. showed that such high concentrations of D-2HG could act as a direct inhibitor of lactate dehydrogenase in mouse T cells. Inhibition of this metabolic enzyme altered glucose metabolism in the T cells and inhibited their proliferation, cytokine production, and ability to kill target cells. See also Oxidoreductase Myelodysplastic syndrome#IDH1 and IDH2 mutations Oncometabolism