TY - JOUR
T1 - L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
AU - Intlekofer, Andrew M.
AU - Wang, Bo
AU - Liu, Hui
AU - Shah, Hardik
AU - Carmona-Fontaine, Carlos
AU - Rustenburg, Ariën S.
AU - Salah, Salah
AU - Gunner, M. R.
AU - Chodera, John D.
AU - Cross, Justin R.
AU - Thompson, Craig B.
N1 - Funding Information:
We thank members of the Thompson laboratory for helpful discussions. We thank M. Isik, S. Hanson, and A. Rizzi from the Chodera laboratory for assistance. A.M.I. was supported by the NIH/NCI (K08 CA201483-01A1), the Leukemia & Lymphoma Society (Special Fellow Award 3356-16), the Burroughs Wellcome Fund (Career Award for Medical Scientists 1015584), the Conquer Cancer Foundation of ASCO, the Susan and Peter Solomon Divisional Genomics Program, and the Steven A. Greenberg Fund. The work was also supported, in part, by the Leukemia & Lymphoma Society Specialized Center of Research Program (7011-16), the Starr Cancer Consortium (I6-A616), and grants from the NIH, including R01 CA168802-02 and R01 CA177828-02 (C.B.T.), K99 CA191021-01A1 (C.C.-F.), and the Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748). M.R.G. and S.S. received financial support from the National Science Foundation (MCB 1022208) and infrastructure support from the National Institute on Minority Health and Health Disparities (8G12MD007603-29).
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nchembio.2307
DO - 10.1038/nchembio.2307
M3 - Article
C2 - 28263965
AN - SCOPUS:85014514282
SN - 1552-4450
VL - 13
SP - 494
EP - 500
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 5
ER -