Cancer-associated Isocitrate Dehydrogenase 1 (IDH1) R132H Mutation and d-2-Hydroxyglutarate Stimulate Glutamine Metabolism under Hypoxia

Reitman, Zachary J.; Duncan, Chris; Poteet, Ethan; Winters, Ali; Yan, Liang-Jun; Gooden, David M.; Spasojević, Ivan; Boros, László G.; Yang, Shao Hua; Yan, Hai

doi:10.1074/jbc.m114.575183

Cited by 85 publications

(75 citation statements)

References 33 publications

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“…Jaisson et al (2009) have shown that the mono γ-methyl ester of α-ketoglutarate is also an excellent substrate of mouse ω-amidase (Kranendijk et al 2010 and references cited therein). It is of considerable interest that many cancers carry a mutation in cytosolic NADP + -dependent isocitrate dehydrogenase that results in a gain-of-function, such that the enzyme catalyzes the non-physiological conversion of α-ketoglutarate to d-HG (e.g., Reitman et al 2014;Rakheja et al 2015).…”

Section: Possible Role Of ω-Amidase As a Repair Enzymementioning

confidence: 99%

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

et al. 2015

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In mammals, two major routes exist for the metabolic conversion of L-glutamine to α-ketoglutarate. The most widely studied pathway involves the hydrolysis of L-glutamine to L-glutamate catalyzed by glutaminases, followed by the conversion of L-glutamate to α-ketoglutarate by the action of an L-glutamate-linked aminotransferase or via the glutamate dehydrogenase reaction. However, another major pathway exists in mammals for the conversion of L-glutamine to α-ketoglutarate (the glutaminase II pathway) in which L-glutamine is first transaminated to α-ketoglutaramate (KGM) followed by hydrolysis of KGM to α-ketoglutarate and ammonia catalyzed by an amidase known as ω-amidase. In mammals, the glutaminase II pathway is present in both cytosolic and mitochondrial compartments and is most prominent in liver and kidney. Similarly, two routes exist for the conversion of L-asparagine to oxaloacetate. In the most extensively studied pathway, L-asparagine is hydrolyzed to L-aspartate by the action of asparaginase, followed by transamination of L-aspartate to oxaloacetate. However, another pathway also exists for the conversion of L-asparagine to oxaloacetate (the asparaginase II pathway). In this pathway, L-asparagine is first transaminated to α-ketosuccinamate (KSM), followed by hydrolysis of KSM to oxaloacetate by the action of ω-amidase. One advantage of both the glutaminase II and the asparaginase II pathways is that they are irreversible, and thus are important in anaplerosis by shuttling 5-C (α-ketoglutarate) and 4-C (oxaloacetate) units into the TCA cycle. In this review, we briefly mention the importance of the glutaminase II and asparaginase II pathways in microorganisms and plants. However, the major emphasis of the review is related to the importance of these pathways (especially the common enzyme component of both pathways--ω-amidase) in nitrogen and sulfur metabolism in mammals and as a source of anaplerotic carbon moieties in rapidly dividing cells. The review also discusses a potential dichotomous function of ω-amidase as having a role in tumor progression. Finally, the possible role of KGM as a biomarker for hyperammonemic diseases is discussed.

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Section: Possible Role Of ω-Amidase As a Repair Enzymementioning

confidence: 99%

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

et al. 2015

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“…Therefore, the present study has provided additional evidence for the reductive carboxylation pathway (17,18), which has recently become somewhat controversial (38). It was shown recently that isotopic labeling in citrate can occur from glutamine through isotopic exchange without net flux through the reductive pathway (39). This could be due to the reversibility of all the metabolic steps between ␣-ketoglutarate and citrate (Fig.…”

Section: Discussionmentioning

confidence: 89%

Inhibition of Neuronal Cell Mitochondrial Complex I with Rotenone Increases Lipid β-Oxidation, Supporting Acetyl-Coenzyme A Levels

Worth

Basu

Snyder

et al. 2014

Journal of Biological Chemistry

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Background: Rotenone exposure is associated with Parkinson disease in humans and rodents, although the exact mechanism remains unknown. Results: Rotenone increased lipid breakdown and glutamine utilization. Conclusion: Metabolic shifts compensated for impaired energy production in response to rotenone. Significance: Metabolic abnormalities associated with mitochondrial dysfunction may play an important role in the development of neurodegeneration.

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“…Glutamine can contribute to 2-HG synthesis through conversion to ␣-KG, via glutaminase (GLS-1) and glutamate dehydrogenase in cancer cells (20,28,32). Therefore, we next evaluated this pathway in our PKD model.…”

Section: Resultsmentioning

confidence: 99%

“…The majority of 2-HG overproduction in cancer has been linked to mutant IDH1 or -2 in cancer, producing 2-HG from glutamine-derived ␣-KG and resulting in an increased flux through the glutamine pathway (20,28). However, 2-HG was also found to aberrantly accumulate in 1) breast cancer with c-Myc overexpression (28); 2) mutations in the genes encoding the D-2-hydroxyglutarate dehydrogenase (D2HGDH) and phosphoglycerate dehydrogenase (PHGDH) enzymes (5,25); and 3) hypoxic cancer cells due to increased levels of WT IDH2 and glutamine-sourced citrate (32).…”

Section: Resultsmentioning

confidence: 99%

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate

Hwang

Kim

Rand

et al. 2015

American Journal of Physiology-Renal Physiology

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LM, Weiss RH. The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate. Am J Physiol Renal Physiol 309: F492-F498, 2015. First published July 8, 2015 doi:10.1152/ajprenal.00238.2015.-Since polycystic kidney disease (PKD) was first noted over 30 years ago to have neoplastic parallels, there has been a resurgent interest in elucidating neoplasia-relevant pathways in PKD. Taking a nontargeted metabolomics approach in the B6(Cg)-Cys1 cpk/ J (cpk) mouse model of recessive PKD, we have now characterized metabolic reprogramming in these tissues, leading to a glutamine-dependent TCA cycle shunt toward total 2-hydroxyglutarate (2-HG) production in cpk compared with B6 wild-type kidney tissue. After confirmation of increased 2-HG expression in immortalized collecting duct cpk cells as well as in human autosomal recessive PKD tissue using targeted analysis, we show that the increase in 2-HG is likely due to glutamine-sourced ␣-ketoglutarate. In addition, cpk cells require exogenous glutamine for growth such that inhibition of glutaminase-1 decreases cell viability as well as proliferation. This study is a demonstration of the striking parallels between recessive PKD and cancer metabolism. Our data, once confirmed in other PKD models, suggest that future therapeutic approaches targeting this pathway, such as using glutaminase inhibitors, have the potential to open novel treatment options for renal cystic disease. ARPKD; glutamine; metabolomics; oncometabolite; reprogramming THE POLYCYSTIC KIDNEY DISEASES (PKD) are disorders characterized by, among other signaling events, dysregulated renal tubular epithelial (RTE) cell proliferation. While the concept that PKD is a "neoplasia in disguise" was initially suggested by Grantham in 1990 (9), it is becoming increasingly clear that the cystic renal diseases have marked biochemical similarities with many aspects of the malignant process (22). Consequently, PKD is now being investigated in the context of tumor metabolism with an eye toward discovery of new therapies and/or repurposing of currently approved or pipeline oncology drugs. Indeed, recent studies in our and other laboratories have shown connections between the cyclin-dependent kinases (1,17,18) and nuclear transport (26) inhibitors in PKD, as well as a striking parallel of metabolic reprogramming related to glycolysis and the Warburg effect, which was shown to occur in an autosomal dominant PKD model (21).Given the current emphasis on the metabolic changes associated with oncogenesis, and since we have successfully utilized metabolomics to discover biomarkers and altered metabolic pathways in renal cell carcinoma (RCC) (8, 30), we took a nontargeted metabolomics approach to compare cancer with autosomal recessive PKD (ARPKD) metabolic pathways. We evaluated the three "matrices" (kidney tissue, serum, and urine) in the B6(Cg)-Cys1 cpk/ J (cpk) mouse model of recessive PKD (10) and then validated the changes in human ARPKD tissue and unaffected contro...

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Cancer-associated Isocitrate Dehydrogenase 1 (IDH1) R132H Mutation and d-2-Hydroxyglutarate Stimulate Glutamine Metabolism under Hypoxia

Cited by 85 publications

References 33 publications

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

ω-Amidase: an underappreciated, but important enzyme in l-glutamine and l-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases

Inhibition of Neuronal Cell Mitochondrial Complex I with Rotenone Increases Lipid β-Oxidation, Supporting Acetyl-Coenzyme A Levels

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate

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