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

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 similarHere 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.Cellular metabolism has been hypothesized to play a central role in cancer since the observation made almost a century ago by Otto Warburg (Warburg 1956) that cancer cells preferentially generate energy by metabolizing glucose to lactate. Even in the presence of oxygen, cancer cells switch from generating ATP by the highly energy-efficient process of oxidative phosphorylation to the much less efficient process of glycolysis (Vander Heiden et al. 2009;Dang 2012). Why this switch occurs has long been a mystery, although the observation that normal cells use ''aerobic glycolysis'' during periods of increased proliferation supports the hypothesis that this metabolic switch is an important feature of rapidly dividing cells (Locasale and Cantley 2011;Lunt and Vander Heiden 2011). Recent work suggests that aerobic glycolysis facilitates cellular transformation by producing the high levels of glycolytic intermediates that proliferating cells need for the biosynthesis of lipids, amino acids, and nucleic acids. Moreover, metabolic reprogramming appears to be sufficient to mediate tumorigenesis in some systems (Lyssiotis and Cantley 2012;Sebastian et al. 2012). Nevertheless, whether altered cellular metabolism is a cause of cancer or merely an adaptive response of cancer cells in the face of accelerated cell proliferation is still a topic of some debate.The recent identification of cancer-associated mutations in three metabolic enzymes suggests that altered cellular metabolism can indeed be a cause of some cancers (Pollard et al. 2003;King et al. 2006;Raimundo et al. 2011). Two of these enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are bone fide tumor suppressors, and loss-of-function mutations in FH and SDH have been identified in various cancers, including renal cell carcinomas and paragangliomas. The third mutated enzyme, isocitrate dehydrogenase (IDH), is a more complicated case. Mutations in two isoforms of IDH, IDH1 and IDH2, are common in a diverse array of cancers, including gliomas and acute myelogenous leukemia (AML) (Dang et al. 2010). The mutant enzymes are not catalytically inactive. Rather, the cancer-associated mutations alter the catalytic activity of the enzymes such that they produce high levels of a metabolite, (R)-2-hydroxyglutarate [(R)-2HG], which is normally ...

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

“…Lipid metabolism is also deregulated in some cancers and can contribute to their proliferative metabolism [29]. Finally, mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 seem to play important roles especially in gliomas and leukaemias ( [34]; see [35]). IDH1 and IDH2 normally catalyse the interconversion between isocitrate and a-KG (figure 1), but the cancer-associated mutations cause them to instead reduce a-KG to the structurally similar metabolite (R)-2-hydroxyglutarate ((R)-2HG).…”

“…IDH1 and IDH2 normally catalyse the interconversion between isocitrate and a-KG (figure 1), but the cancer-associated mutations cause them to instead reduce a-KG to the structurally similar metabolite (R)-2-hydroxyglutarate ((R)-2HG). 2HG is proposed to act as an 'oncometabolite', suggested to at least in part exert its effects by competing with a-KG for binding to a-KG-regulated proteins with tumour suppressor roles (reviewed in [35]). …”

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

“…In pursuit of drug candidates targeting recurrent oncogenic IDH2 mutations, we initiated a high-throughput screen for inhibitors of the enzyme carrying the most prevalent IDH2 mutation in AML, IDH2 R140Q (29)(30)(31). Several triazine compounds active against the IDH2 R140Q homodimer emerged, and initial hit-to-lead chemistry led to compound 1, the first sub-100 nmol/L inhibitor of IDH2 R140Q (Fig.…”

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

“…The discovery of oncogenic mutations in IDH enzymes demonstrated the profound impact that altered metabolism can have on cell identity and function 1,2 . Mutant IDH enzymes efficiently catalyze reduction of αKG to the ‘oncometabolite’ D-2HG 3,4 .…”

“…Mutant IDH enzymes efficiently catalyze reduction of αKG to the ‘oncometabolite’ D-2HG 3,4 . D-2HG inhibits a large family of >70 different αKG-dependent enzymes that regulate chromatin-modifications, stability of hypoxia-inducible factors, extracellular matrix maturation, and DNA repair 1 . In particular, D-2HG-mediated inhibition of chromatin-modifying enzymes impairs induction of gene expression programs required for normal cell differentiation and ‘locks’ malignant cells in an undifferentiated stem cell-like state 5–7 .…”