Isocitrate dehydrogenase [NADP], mitochondrial is anenzyme that in humans is encoded by theIDH2gene.[5]
Isocitrate dehydrogenases areenzymes that catalyze the oxidativedecarboxylation ofisocitrate to2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizesNAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to themitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantlycytosolic. Each NADP(+)-dependent isozyme is ahomodimer. The protein encoded by the IDH2 gene is the NADP(+)-dependent isocitrate dehydrogenase found in the mitochondria. It plays a role in intermediary metabolism and energy production. This protein may tightly associate or interact with thepyruvate dehydrogenase complex.[5] Somatic mosaic mutations of this gene have also been found associated toOllier disease andMaffucci syndrome.[6]
Isocitrate dehydrogenase is composed of three subunits, allosterically regulated, and requires an integrated Mg2+ or Mn2+ ion. The mitochondrial form of IDH, like most isoforms, is a homodimer, in which two identical monomer subunits form one unit. The structure ofMycobacterium tuberculosis IDH-1 bound with NADPH and Mn2+ has been solved byX-ray crystallography. It is a homodimer in which each subunit has aRossmann fold, and a common top domain of interlockingβ sheets. Mtb IDH-1 is most structurally similar to the R132H mutant human IDH found in certainglioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes the formation ofα-hydroxyglutarate.[7]
Isocitrate dehydrogenase is a digestive enzyme that is used in thecitric acid cycle. Its main function is to catalyze theoxidative decarboxylation of isocitrate intoalpha-ketoglutarate. Human isocitrate dehydrogenase regulation is not fully understood however, it is known that NADP and Ca2+ bind in the active site to create three different conformations. These conformations form in the active site and are as follows: a loop is form in the inactive enzyme, a partially unraveledalpha helix in the semi open form, and an alpha helix in the active form.[8]
The mitochondrial form of IDH2 is correlated with many diseases. Mutations in IDH2 are associated with2-hydroxyglutaric aciduria, a condition that causes progressive damage to thebrain. The major types of this disorder are called D-2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA). The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (thecerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory. Researchers have described two subtypes of D-2-HGA, type I and type II. The two subtypes are distinguished by their genetic cause and pattern of inheritance, although they also have some differences in signs and symptoms. Type II tends to begin earlier and often causes more severe health problems than type I. Type II may also be associated with a weakened and enlarged heart (cardiomyopathy), a feature that is typically not found with type I. L-2-HGA particularly affects a region of the brain called the cerebellum, which is involved in coordinating movements. As a result, many affected individuals have problems with balance and muscle coordination (ataxia). Additional features of L-2-HGA can include delayed development, seizures, speech difficulties, and an unusually large head (macrocephaly). Typically, signs and symptoms of this disorder begin during infancy or early childhood. The disorder worsens over time, usually leading to severe disability by early adulthood. Combined D,L-2-HGA causes severe brain abnormalities that become apparent in early infancy. Affected infants have severe seizures, weak muscle tone (hypotonia), and breathing and feeding problems. They usually survive only into infancy or early childhood.[5]
Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors. As IDH1 and IDH2 represent key enzymes within thetricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism. The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future.[12]
Vorasidenib was approved for medical use in the United States in August 2024.[15][16] Vorasidenib is the first approval by the FDA of a systemic therapy for people with grade 2astrocytoma oroligodendroglioma with a susceptibleisocitrate dehydrogenase-2 or isocitrate dehydrogenase-2 mutation.[15]
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^Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE (December 2014). "The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation".Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.1846 (2):326–41.doi:10.1016/j.bbcan.2014.05.004.PMID24880135.
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