Isocitrate dehydrogenase 1 is an enzyme that in humans is encoded by the IDH1 gene on chromosome 2.
Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the citric acid cycle.
Isocitrate dehydrogenases belong to two distinct subclasses, one of which uses NAD+ as the electron acceptor and the other NADP+.
There are 5 isocitrate dehydrogenases.
Three NAD+-dependent isocitrate dehydrogenase, localized to the mitochondrial matrix, and
Two NADP+-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic.
IDH1 is one of three isocitrate dehydrogenase isozymes, the other two being IDH2 and IDH3.
The isocitrate dehydrogenase enzymes are encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G.
Its conformational changes at the active sites affect the activity of the enzyme.
It targets the protein to the peroxisome.
As an isocitrate dehydrogenase, IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate allowing for the concomitant reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced nicotinamide adenine dinucleotide phosphate (NADPH).
Since NADPH functions in cellular detoxification processes in response to oxidative stress, IDH1 also indirectly participates in mitigating oxidative damage.
IDH1 is key to oxidation of unsaturated fatty acids in the peroxisomes of liver cells.
IDH1 participates in the regulation of glucose-induced insulin secretion.
IDH1 is the primary producer of NADPH in most tissues, especially in brain.
IDH1 is localized to the cytoplasm, peroxisome, and endoplasmic reticulum.
Under hypoxic conditions, IDH1 contributes to citrate production via glutaminolysis.
IDH1 mutations are heterozygous, typically involving an amino acid substitution in the active site of the enzyme in codon 132.
IDH1 mutations result in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate.
2-hydroxyglutarate inhibits enzymatic function of many alpha-ketoglutarate dependent dioxygenases: causing widespread changes in histone and DNA methylation and potentially promoting tumorigenesis.
IDH1 mutations cause metaphyseal chondromatosis with aciduria.
Mutations in IDH1 were detected in genomic analysis of human glioblastoma multiforme.
Mutations in the genes encoding metabolic enzymes isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are present in nearly all grade 2 diffuse gliomas in adults.
Mutations in IDH1 and its homologue IDH2 are among the most frequent mutations in diffuse gliomas, including: diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma, and secondary glioblastoma.
Mutations in IDH1 are often the first hit in the development of diffuse gliomas.
IDH1 mutations are detected in approximately 13% of intrahepatic cholangiocarcinomas.
Glioblastomas with a wild-type IDH1 gene have a median overall survival of only 1 year, whereas IDH1-mutated glioblastoma patients have a median overall survival of over 2 years.
Tumors of various tissue types with IDH1/2 mutations show improved responses to radiation and chemotherapy.
The mutation in IDH1 is R132H, which acts as a tumor suppressor.
IDH1 harbors mutations in human acute myeloid leukemia.
The IDH1 mutation drives alterations and occurs early during tumorigenesis in glioma and glioblastoma multiforme.
In patients with grade2 IDH-mutant glioma, Vorasidenib denib significantly improved progression free survival and delays the time to the next intervention.
Ivosidenib was approved by the FDA in for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.
Approximately 20-25% of patients with AML have an IDH1 or IDH2 mutation.
IDH2 mutations are more common than IDH1 mutations in AML, occurring in approximately 15-20% of patients.
In myelodysplastic syndrome IDH Mutations or less common and IDH2 mutations occur in approximately 3-5% of patients and IDH1 mutations are found in approximately 3%.
Two IDH Inhibitors are approved for relapsed or refractory AML: Enasidenib and Ivosidenib for IDH2, and IDH1 mutations, respectively.
Ivosidenib and azacitidine show significant clinical benefit as compared with the placebo and azacytidine in IDH1 AML.
IDH inhibitors work by causing myeloid differentiation.
IGH2 inhibitors may lead to a differentiation syndrome in approximately 10 to 15% of patients.
With the differentiation syndrome the leukemic cells, the myeloid blasts, start to mature and differentiate with the development of pulmonary edema, pleural effusion, and other manifestations of a capillary leak syndrome.