The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases

Chowdhury, Rasheduzzaman; Yeoh, Kar Kheng; Tian, Ya-Min; Hillringhaus, Lars; Bagg, Eleanor A. L.; Rose, Nathan R.; Leung, Ivanhoe K. H.; Li, Xuan S; Woon, Esther C. Y.; Yang, Ming; McDonough, Michael A.; King, Oliver N.; Clifton, I.J.; Klose, Robert J.; Claridge, Timothy D. W.; Ratcliffe, Peter J.; Schofield, Christopher J.; Kawamura, Akane

doi:10.1038/embor.2011.43

Cited by 894 publications

(910 citation statements)

References 31 publications

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“…11). Thus, we conclude that acid-enhanced L-2HG production stabilizes HIF-1α by inhibiting the αKG-dependent prolyl hydroxylases that target HIF-1α for degradation, in agreement with previously observed effects of L-2HG on prolyl hydroxylases in vitro 11,13 .…”

Section: Resultssupporting

confidence: 92%

“…Compared to L-2HG, we observed approximately 10 fold lower intracellular concentrations of D-2HG. Given that L-2HG functions as a more potent inhibitor of αKG-dependent enzymes than D-2HG 11–13 , we conclude that D-2HG derived from wildtype IDH and/or PHGDH is negligible and likely does not play a physiologic role in this setting.…”

Section: Discussionmentioning

confidence: 87%

“…L-2HG acts to stabilize hypoxia-inducible factors by inhibiting the αKG-dependent prolyl hydroxylases that target HIF for degradation 11,13 . Whether HIF-1α stabilization is a qualitatively or quantitatively unique property of L-2HG compared to D-2HG remains controversial 13,47,48 .…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, biochemical assays demonstrated that L-2HG functions as a more potent inhibitor of αKG-dependent enzymes compared to D-2HG; thus cells may be quantitatively more sensitive to changes in L-2HG than D-2HG 11–13 . Indeed, deregulated L-2HG disposal causes significant developmental pathology and is associated with brain and kidney cancer 14–16 .…”

mentioning

confidence: 99%

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

et al. 2017

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The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase 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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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2017

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“…Much like SDH‐ and FH‐mutated tumors, IDH‐mutated cells and tumors have been shown to exhibit a hypermethylator phenotype through the inhibition of the ten‐eleven translocation (TET) family of DNA demethylases and members of the Jumonji C‐domain histone demethylases through the competitive inhibition of αKG binding by (R)‐2HG 105, 106, 107, 108, 109. However, unlike SDH and FH mutations, the effect of (R)‐2HG on PHD activity has been the subject of some controversy.…”

Section: Mutations Of Mitochondrial (And Associated) Metabolic Enzymementioning

confidence: 99%

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

Hollinshead

Tennant

2016

WIREs Mechanisms of Disease

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Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia‐induced changes in the proteome mediated by the activity of transcription factors such as hypoxia‐inducible factor 1. Hypoxia is a well‐described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer‐associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272–285. doi: 10.1002/wsbm.1334For further resources related to this article, please visit the WIREs website.

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IDHMutation in Glioma

2014

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EVIDENCE REVIEW A systematic review of the literature dating from 2008, when IDH mutation was discovered to be clinically significant in glioma, to 2013 was performed using the PubMed database. The following search terms were used: IDH, IDH1, IDH2, and isocitrate dehydrogenase, in conjunction with glioma or leukemia. The search was limited to articles published in English. Further hand searching was performed using a review of the pertinent references from the identified publications. All identified original articles were investigated for content and critiqued by Z.T. and S.D.FINDINGS IDH mutation is an early event in gliomagenesis and has significant implications for glioma progression and tumor behavior. Early evidence suggests that IDH may be a therapeutic target in IDH-mutant gliomas. CONCLUSIONS AND RELEVANCEIDH mutation is a central and defining event in the development and progression of glioma and may be a key target for future therapies for these types of neoplasms.

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The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases

Cited by 894 publications

References 31 publications

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

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

Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

IDHMutation in Glioma

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