Enzymes Adopt New M.O. in Cancer

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Science  12 Mar 2010:
Vol. 327, Issue 5971, pp. 1305
DOI: 10.1126/science.327.5971.1305-b

Identification of genes that are recurrently mutated in human tumors can potentially lead to new cancer treatments, but first we need to understand how the mutations alter the biochemical activity of the encoded protein and contribute to tumor development and progression. The recent discovery that a subset of human brain tumors harbor mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) has focused interest on this cytosolic metabolic enzyme and its mitochondrial homolog IDH2. Mutations in these genes have been detected in acute myeloid leukemia that always alter the same amino acid in the enzymes' catalytic sites and are always present in heterozygous form, suggesting that tumor cells contain “normal,” as well as mutant, versions of the enzymes. Ward et al. and Dang et al. now show how the tumor-associated mutations alter the biochemical activity of IDH1 and IDH2. The mutant enzymes not only lose their normal activity (the conversion of isocitrate to α-ketoglutarate) but also acquire a new activity: the reduction of α-ketoglutarate to 2-hydroxyglutarate. Indeed, elevated levels of 2-hydroxyglutarate were detected in human tumor samples that contained either IDH1 or IGH2 mutations. Determining how 2-hydroxyglutarate, a so-called “oncometabolite,” contributes to the biology of brain tumors and leukemia will be an important next step in moving from mutant gene to therapy.

Cancer Cell 17, 1 (2010); Nature 462, 739 (2009).

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