Cancer-associated mutation and beyond

The emerging biology of isocitrate dehydrogenases in human disease

Serena Tommasini-Ghelfi, Kevin Murnan, Fotini M. Kouri, Akanksha S. Mahajan, Jasmine L. May, Alexander H Stegh*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Isocitrate dehydrogenases (IDHs) are critical metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), NAD(P)H, and CO2. IDHs epigenetically control gene expression through effects on αKG-dependent dioxygenases, maintain redox balance and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis, and regulate respiration and energy production through generation of NADH. Cancer-associated mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effect. Mutant enzymes produce (R)-2-hydroxyglutarate, which in turn inhibits αKG-dependent dioxygenase function, resulting in a global hypermethylation phenotype, increased tumor cell multipotency, and malignancy. Recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to cancer and neurodegeneration, respectively. We describe how mutant and wild-type enzymes contribute on molecular levels to disease pathogenesis, and discuss efforts to pharmacologically target IDH-controlled metabolic rewiring.

Original languageEnglish (US)
Article numberaaw4543
JournalScience Advances
Volume5
Issue number5
DOIs
StatePublished - Jan 1 2019

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dehydrogenases
mutations
biology
emerging
cancer
enzymes
pathogenesis
decarboxylation
phenotype
physiology
gene expression
regulators
respiration
organs
tumors
synthesis
cells

ASJC Scopus subject areas

  • General
  • Physics and Astronomy (miscellaneous)

Cite this

Tommasini-Ghelfi, Serena ; Murnan, Kevin ; Kouri, Fotini M. ; Mahajan, Akanksha S. ; May, Jasmine L. ; Stegh, Alexander H. / Cancer-associated mutation and beyond : The emerging biology of isocitrate dehydrogenases in human disease. In: Science Advances. 2019 ; Vol. 5, No. 5.
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abstract = "Isocitrate dehydrogenases (IDHs) are critical metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), NAD(P)H, and CO2. IDHs epigenetically control gene expression through effects on αKG-dependent dioxygenases, maintain redox balance and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis, and regulate respiration and energy production through generation of NADH. Cancer-associated mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effect. Mutant enzymes produce (R)-2-hydroxyglutarate, which in turn inhibits αKG-dependent dioxygenase function, resulting in a global hypermethylation phenotype, increased tumor cell multipotency, and malignancy. Recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to cancer and neurodegeneration, respectively. We describe how mutant and wild-type enzymes contribute on molecular levels to disease pathogenesis, and discuss efforts to pharmacologically target IDH-controlled metabolic rewiring.",
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Cancer-associated mutation and beyond : The emerging biology of isocitrate dehydrogenases in human disease. / Tommasini-Ghelfi, Serena; Murnan, Kevin; Kouri, Fotini M.; Mahajan, Akanksha S.; May, Jasmine L.; Stegh, Alexander H.

In: Science Advances, Vol. 5, No. 5, aaw4543, 01.01.2019.

Research output: Contribution to journalArticle

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