What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer (original) (raw)
- William G. Kaelin Jr.1,2,3
- 1Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA;
- 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
Abstract
Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.
- 2-oxoglutarate-dependent dioxygenase
- cancer metabolism
- chondrosarcoma
- glioma
- isocitrate dehydrogenase
- leukemia
Footnotes
↵3 Corresponding author
E-mail william_kaelin{at}dfci.harvard.eduArticle is online at http://www.genesdev.org/cgi/doi/10.1101/gad.217406.113.
Copyright © 2013 by Cold Spring Harbor Laboratory Press