Journal Article

Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism

Zachary J. Reitman and Hai Yan

in JNCI: Journal of the National Cancer Institute

Published on behalf of National Cancer Institute

Volume 102, issue 13, pages 932-941
Published in print July 2010 | ISSN: 0027-8874
Published online July 2010 | e-ISSN: 1460-2105 | DOI: http://dx.doi.org/10.1093/jnci/djq187
Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism

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Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP+-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2–4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.

Journal Article.  6862 words.  Illustrated.

Subjects: Medical Oncology

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