What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

Losman, Julie-Aurore; Kaelin, William G.

doi:10.1101/gad.217406.113

PreprintCited by 570Cancer, Hypoxia, and MetabolismGlioma Diagnosis and TreatmentAcute Myeloid Leukemia Research

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

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Losman, Julie-Aurore, Kaelin, William G.·2013·Genes & Development

DOI 10.1101/gad.217406.113PMC PMC3650222

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Abstract

Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similar metabolite (R)-2-hydroxyglutarate [(R)-2HG]. Here we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.

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De novo neomorphic IDH mutations promote aberrant DNA methylation by increased production of 2-hydroxyglutarate (2HG), which inhibits the hydroxylation of 5-methylcytosine (5mC), a reaction catalysed by TET2.
“One unifying notion is that de novo neomorphic IDH mutations promote aberrant DNA methylation by increased production of 2-hydroxyglutarate (2HG),2 which inhibits the hydroxylation of 5-methylcytosine (5mC), a reaction catalysed by TET2.”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [2]
Succinate inhibits the hydroxylation of HIF-1α by EGLN1, resulting in pseudohypoxic HIF-1α stabilization under normoxic conditions.
“Succinate inhibits the hydroxylation of HIF-1␣ by EGLN1, resulting in pseudohypoxic HIF-1␣ stabilization under normoxic conditions (10 -12).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [12]

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“, 2011), although D2HG has also been shown to activate PHD (Koivunen et al., 2012; Losman et al., 2013).”
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Authors: Losman, J.-A., & Kaelin, W. G.
Affiliations: Brigham and Women's Hospital (US)
ORCID: Losman, Julie-Aurore
Kaelin, William G.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2013-04-15
Volume: 27
Issue: 8
Pages: 836-852
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.217406.113
PMC: PMC3650222
OpenAlex: W2164219809
Cited by: 570
References: 186
Citations by year: 2026: 20 · 2025: 27 · 2024: 34 · 2023: 33 · 2022: 40 · 2021: 56 · 2020: 55 · 2019: 50 · 2018: 41 · 2017: 61 · 2016: 50 · 2015: 39 · 2014: 51 · 2013: 13
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
Breast Cancer Research Foundation
FibroGen
Agios Pharmaceuticals
National Institutes of Health
National Cancer Institute (F31CA260794, R01CA068490, R01CA076120)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords: isocitrate dehydrogenase, IDH1, IDH2, (R)-2-hydroxyglutarate, alpha-ketoglutarate, cancer metabolism, carcinogenesis, targeted therapy
MeSH terms: Animals, Catalysis, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, Neoplasms, Oncogenes

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What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

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