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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
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Journal Article
L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
2017
Overview
Acidification enhances lactate dehydrogenase– and malate dehydrogenase–mediated promiscuous production of
L
-2-hydroxyglutarate (
L
-2HG) from α-ketoglutarate and stabilizes HIF-1α levels.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
