L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH.

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L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH.

Nat Chem Biol. 2017 05;13(5):494-500

Authors: Intlekofer AM, Wang B, Liu H, Shah H, Carmona-Fontaine C, Rustenburg AS, Salah S, Gunner MR, Chodera JD, Cross JR, Thompson CB

Abstract
The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) 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 protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

PMID: 28263965 [PubMed – indexed for MEDLINE]