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Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates
Dan Ye1, Kun-Liang Guan2, Yue Xiong3
1Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Abstract:
Isocitrate dehydrogenases (IDH1/2) are frequently mutated in multiple types of human cancer, resulting in neomorphic enzymes that convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). The current view on the mechanism of IDH mutation holds that 2-HG acts as an antagonist of α-KG to competitively inhibit the activity of α-KG-dependent dioxygenases, including those involved in histone and DNA demethylation. Recent studies have implicated 2-HG in activities beyond epigenetic modification. Multiple enzymes have been discovered that lack mutations but that can nevertheless produce 2-HG promiscuously under hypoxic or acidic conditions. Therapies are being developed to treat IDH-mutant cancers by targeting either the mutant IDH enzymes directly or the pathways sensitized by 2-HG.
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