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Full-Text Articles in Life Sciences
L-2-Hydroxyglutarate Production Arises From Non-Canonical Enzyme Function At Acidic Ph, Andrew M. Intlekofer, Bo Wang, Hui Liu, Hardik Shah, Carlos Carmona-Fontanie, Ariën S. Rustenburg, Salah Salah, Marilyn R. Gunner, John D. Chodera, Justin R. Cross, Craig B. Thompson
L-2-Hydroxyglutarate Production Arises From Non-Canonical Enzyme Function At Acidic Ph, Andrew M. Intlekofer, Bo Wang, Hui Liu, Hardik Shah, Carlos Carmona-Fontanie, Ariën S. Rustenburg, Salah Salah, Marilyn R. Gunner, John D. Chodera, Justin R. Cross, Craig B. Thompson
Publications and Research
The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a …