Isocitrate dehydrogenase (IDH) is an important enzyme in the tricarboxylic acid cycle, which occurs in the mitochondrial matrix. IDH is responsible for catalyzing the reversible conversion of isocitrate to alpha-ketoglutarate and CO2 in a two-step reaction. The first step of the reaction involves the oxidation of isocitrate to the intermediate oxalosuccinate. The second step of the reaction looses the beta-carboxylate of the oxalosuccinate intermediate as carbon dioxide leaving alpha-ketogluterate. During the catalyzation of isocitrate to alpha ketoglutarate either NADH or NADPH is produced along with carbon dioxide.
An overview of IDH
Isocitrate dehydrogenase (IDH) is a critical enzyme involved in the tricarboxylic acid cycle, catalyzing the conversion of isocitrate to α-ketoglutarate (αKG), which is rate-limit process in the Krebs cycle. IDH mutation in somatic cells will lead to the loss of this function, and convertsαKG into tumor metabolite D-2-hydroxpentanoic acid resulting DNA or histone hypermethylation.
Major types of IDH
There are three members in the family of IDHs : IDH1, IDH2 and IDH3, and all of them are able to catalyze the oxidative decarboxylation of isocitrate to produceαKG and CO2. Mg2+ or Mn2+ and the cofactors NADP+ or NAD+ are the electron acceptors in these processes, and generate NADPH or NADH. The structures of IDH1 and IDH2 are similar, belonging to the NADP+-dependent family with different subcellular localization of the two proteins. IDH3, mitochondrial isoforms of IDH, is composed of three types of subunits: IDH3A, IDH3B, IDH3G.
Inhibition of IDH
According to the target, IDH inhibitors can be divided into three categories: IDH1 inhibitors, IDH2 inhibitors and IDH1 /IDH2 inhibitors. The first IDH1 inhibitor AGI-5918 and IDH2 inhibitor AGI-6780 were discovered by Agios. Later on, Agios developed new drugs for the continued perfection of IDH inhibitors, like AG-120, AG-221 and AG-881, and all of them are in clinical use. Other pharmaceutical companies have also developed many inhibitors targeting IDH, such as GSK 321 by GlaxoSmithKline, BAY-1436032 by Bayer, IDH305 by Novartis and FT-2012 by Forma Therapeutics.
IDH and diseases
IDH mutation can be discovered in many diseases, such as low-grade glioma, secondary malignant glioma, melanoma, angioimmunoblastic T-cell lymphoma, myeloproliferative neoplasms, myelodysplastic syndrome and acute myelocytic leukemia. The discovery of somatic mutation in the IDH enzymes is of great significance in cancer biology, making IDH a rational target for the treatment of cancer.
1. Wang, H. Y., Ye, Z. & Liu, X. K. Research progress of isocitrate dehydrogenase inhibitors. Chinese Journal of New Drugs 26, 1272-1278 (2017).
2. Yen, K. E., Bittinger, M. A., Su, S. M. & Fantin, V. R. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene 29, 6409 (2010).
3. Medeiros, B. C. et al. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia 31, 272-281 (2017).