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L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
Open accessAbstract
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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“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]
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“Malonate itself was also protective when added at reperfusion152,153.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [152]
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“Later, the same research group also demonstrated that the L-2HG produced by LDHA is favored in an acidic environment and promotes the HIF 1-α stabilization under normoxia conditions (78).”
Background
Metadata
- 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
- Venue
- Nature Chemical Biology
- Published
- 2017-03-06
- Volume
- 13
- Issue
- 5
- Pages
- 494-500
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- 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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