Cited by 243Cancer, Hypoxia, and MetabolismBiochemical Acid Research StudiesGlioma Diagnosis and Treatment

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Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates

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Ye, Dan, Guan, Kun-Liang, Xiong, Yue·2018·Trends in Cancer

DOI 10.1016/j.trecan.2017.12.005PMC PMC5884165

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Abstract

Isocitrate dehydrogenases (IDH1/2) are frequently mutated in multiple types of human cancer, resulting in neomorphic enzymes that convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). The current view on the mechanism of IDH mutation holds that 2-HG acts as an antagonist of α-KG to competitively inhibit the activity of α-KG-dependent dioxygenases, including those involved in histone and DNA demethylation. Recent studies have implicated 2-HG in activities beyond epigenetic modification. Multiple enzymes have been discovered that lack mutations but that can nevertheless produce 2-HG promiscuously under hypoxic or acidic conditions. Therapies are being developed to treat IDH-mutant cancers by targeting either the mutant IDH enzymes directly or the pathways sensitized by 2-HG.

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Figure 1 Metabolism and Targets of 2-Hydroxyglutarate (2-HG) The thick and thin arrows represent the primary and promiscuous reactions, respectively. FAD, flavin adenine dinucleotide; FADH2, reduced form of FAD; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of NADP. Additional abbreviations are listed in Table 1.CC BY-NC-ND · PubMed Central

Figure 2 Production of 2-Hydroxyglutarate (2-HG) by Promiscuous Enzymatic Reactions The thick and thin arrows represent the primary and promiscuous reactions, respectively. PHDGH, phosphoglycerate dehydrogenase; 3PG, 3-phosphoglycerate; 3PHP, 3-phosphohydroxypyruvate. Additional abbreviations are listed in Figure 1.CC BY-NC-ND · PubMed Central

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Authors: Ye, D., Guan, K.-L., & Xiong, Y.
Affiliations: Shanghai Medical College of Fudan University (CN)
University of North Carolina at Chapel Hill (US)
Corresponding author: Ye, Dan
Xiong, Yue
ORCID: Ye, Dan
Guan, Kun-Liang
Xiong, Yue
Venue: Trends in Cancer
Publisher: Elsevier BV
Published: 2018-02
Volume: 4
Issue: 2
Pages: 151-165
ISSN: 2405-8025 (ISSN-L)
2405-8033
DOI: 10.1016/j.trecan.2017.12.005
PMC: PMC5884165
OpenAlex: W2782192099
Cited by: 242
References: 138
Citations by year: 2026: 26 · 2025: 31 · 2024: 23 · 2023: 28 · 2022: 30 · 2021: 38 · 2020: 29 · 2019: 25 · 2018: 11
FWCI: 2.69
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Trends in cancer (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
PubMed Central (acceptedVersion, cc-by-nc-nd)
eScholarship (California Digital Library) (submittedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders: National Key R&D Program of China (2016YFA0501800)
NSFC (81522033, 81372198)
Shanghai Committee of Science and Technology (16JC1404000)
NIH (CA196878, GM51586, CA063834, CA163834)
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
Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
Keywords: 2-hydroxyglutarate, IDH mutation, IDH1, IDH2, alpha-ketoglutarate, epigenetic demethylation, histone demethylation, DNA demethylation, hypoxia, acidosis
MeSH terms: Animals, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, Neoplasms, Molecular Targeted Therapy

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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.

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Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates

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