Cited by 268Cancer, Hypoxia, and MetabolismBiochemical Acid Research StudiesAmino Acid Enzymes and Metabolism

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

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Intlekofer, Andrew M, Wang, Bo, Liu, Hui, Shah, Hardik, Carmona-Fontaine, Carlos, Rustenburg, Ariën S, Salah, Salah, Gunner, M R, Chodera, John D, Cross, Justin R, Thompson, Craig B·2017·Nature Chemical Biology

DOI 10.1038/nchembio.2307PMC PMC5516644

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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.

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Authors: 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.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
City College of New York (US)
Corresponding author: Thompson, Craig B
ORCID: Intlekofer, Andrew M
Wang, Bo
Shah, Hardik
Rustenburg, Ariën S
Gunner, M R
Chodera, John D
Cross, Justin R
Thompson, Craig B
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2017-03-06
Volume: 13
Issue: 5
Pages: 494-500
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.2307
PMC: PMC5516644
OpenAlex: W2594191418
Cited by: 268
References: 63
Citations by year: 2026: 21 · 2025: 29 · 2024: 28 · 2023: 25 · 2022: 28 · 2021: 40 · 2020: 27 · 2019: 28 · 2018: 26 · 2017: 14
FWCI: 8.72
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
CUNY Academic Works (City University of New York) (submittedVersion)
Funders: National Cancer Institute (R00CA191021, K08CA201483, K99CA191021, R01CA177828, R01CA168802, P30CA008748)
National Institute on Minority Health and Health Disparities (G12MD007603)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: L-2-hydroxyglutarate, lactate dehydrogenase, malate dehydrogenase, stereospecific reduction, alpha-ketoglutarate, low pH, protonation, substrate binding pocket, hypoxia, HIF-1α stabilization, IDH mutation, oxygen limitation, tumor microenvironment
MeSH terms: Glutarates, Humans, Hydrogen-Ion Concentration, Ketoglutaric Acids, L-Lactate Dehydrogenase, Malate Dehydrogenase, Gas Chromatography-Mass Spectrometry, Stereoisomerism, Molecular Structure, Biocatalysis

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

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