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

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

Open access
Intlekofer, Andrew M, Wang, Bo, Liu, Hui, Shah, Hardik, Carmona-Fontaine, Carlos, Rustenburg, Ariën S, Salah, Salah, Gunner, M R +3 more·2017·Nature Chemical Biology

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nchembio.2307

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • L-2-HG accumulation in an acidic pH environment results in HIF-1α stabilization in normoxia.

    “In addition, L-2-HG accumulation in an acidic pH environment has been reported to result in HIF-1α stabilization in normoxia91 (Fig. 4).”

    From Glutamine reliance in cell metabolism (2020) · cites this paper as [91]

  • Malonate is protective when added at reperfusion.

    “Malonate itself was also protective when added at reperfusion152,153.”

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
Venue
Nature Chemical Biology
Published
2017-03-06
Volume
13
Issue
5
Pages
494-500
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review