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Nat Chem Biol. 2017 May;13(5):494-500. doi: 10.1038/nchembio.2307. Epub 2017 Mar 6.

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

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
4
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Physics Department, City College of New York, New York, New York, USA.

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
PMCID:
PMC5516644
DOI:
10.1038/nchembio.2307
[Indexed for MEDLINE]
Free PMC Article

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