Isocitrate dehydrogenases catalyze the
oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 localizes to
the cytoplasm and peroxisomes, and acts as a NADP-dependent protein that
catalyzes decarboxylation of isocitrate into alpha-ketoglutarate. The
homologous isocitrate dehydrogenase 2 (IDH2) is the only protein homologous to
IDH1 that also utilizes NADP; however IDH2 localizes to the mitochondria. IDH2
plays an important role in controlling the mitochondrial redox balance, and in
providing protection from oxidative damage similar to IDH1.
Several recent studies have identified a
genetic alteration in the IDH1 or IDH2 genes of malignant brain tumors. While
IDH1 or IDH2 mutations are observed in the majority of grade II and III
astrocytomas and oligodendrogliomas, glioblastomas and low grade astrocytic
tumors demonstrate an absence or low frequency of mutations.
All IDH alterations are point mutations
resulting in a “missense” change at codon 132 of IDH1, and codons 140 or 172 of
IDH2. Residues 132 of IDH1 and 172 of IDH2 are analogous between genes, and
occur in exon 4 at a highly conserved region of the isocitrate binding site.
The mutation is thought to down-regulate or even eliminate enzyme activity,
leading to increased cellular oxidative stress and damage.
IDH1 or IDH2 mutations have also been
observed in about 10% of acute myeloid leukemia (AML) cases.
References (open access):
Isocitrate dehydrogenase 1 and 2 mutations in cancer:
alterations at a crossroads of cellular metabolism. Reitman ZJ, Yan H. J Natl
Cancer Inst. 2010 Jul 7;102(13):932-41.
IDH1 and IDH2 gene mutations identify novel molecular
subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer
and Leukemia Group B study. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrózek
K, Margeson D, Holland KB, Whitman SP, Becker H, Schwind S, Metzeler KH, Powell
BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Caligiuri MA, Larson
RA, Bloomfield CD. J Clin Oncol. 2010 May 10;28(14):2348-55.