Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 19, Pages 7971-7983Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.776179
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Funding
- National Institute of Health [K99 CA187594, R00 CA187594, 5T34 GM008303, P30 CA030199]
- Summer Undergraduate Research Program Grant from San Diego State University
- San Diego State University startup funds
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Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP(+) -dependent conversion of isocitrate (ICT) to alpha-ketoglutarate (alpha KG) in the cytosol and peroxisomes. Mutations in IDH1 have been implicated in >80% of lower grade gliomas and secondary glioblastomas and primarily affect residue 132, which helps coordinate substrate binding. However, other mutations found in the active site have also been identified in tumors. IDH1 mutations typically result in a loss of catalytic activity, but many also can catalyze a new reaction, the NADPH-dependent reduction of alpha KG to D-2-hydroxyglutarate (D2HG). D2HG is a proposed oncometabolite that can competitively inhibit alpha KG-dependent enzymes. Some kinetic parameters have been reported for several IDH1 mutations, and there is evidence that mutant IDH1 enzymes vary widely in their ability to produce D2HG. We report that most IDH1 mutations identified in tumors are severely deficient in catalyzing the normal oxidation reaction, but that D2HG production efficiency varies among mutant enzymes up to similar to 640-fold. Common IDH1 mutations have moderate catalytic efficiencies for D2HG production, whereas rarer mutations exhibit either very low or very high efficiencies. We then designed a series of experimental IDH1 mutants to understand the features that support D2HG production. We show that this new catalytic activity observed in tumors is supported by mutations at residue 132 that have a smaller van der Waals volume and are more hydrophobic. We report that one mutation can support both the normal and neomorphic reactions. These studies illuminate catalytic features of mutations found in the majority of patients with lower grade gliomas.
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