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

Andrew M. Intlekofer, Bo Wang, Hui Liu, Hardik Shah, Carlos Carmona-Fontaine, Ariën S. Rustenburg, Salah Salah, M. R. Gunner, John D. Chodera, Justin R. Cross, Craig B. Thompson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)494-500
Number of pages7
JournalNature Chemical Biology
Volume13
Issue number5
DOIs
StatePublished - May 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Intlekofer, A. M., Wang, B., Liu, H., Shah, H., Carmona-Fontaine, C., Rustenburg, A. S., Salah, S., Gunner, M. R., Chodera, J. D., Cross, J. R., & Thompson, C. B. (2017). L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH. Nature Chemical Biology, 13(5), 494-500. https://doi.org/10.1038/nchembio.2307