C. Corbet, O. Féron
Jul 1, 2015
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Influential Citations
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Journal
Current Opinion in Clinical Nutrition and Metabolic Care
Abstract
Purpose of reviewGlutamine and acetate were recently identified as alternatives to glucose for fueling the tricarboxylic acid (TCA) cycle in cancer cells, particularly in the context of hypoxia. Recent findingsMolecular mechanisms orchestrating glutamine and acetate metabolism were elicited through the combination of 13C tracer analysis and genetic silencing, or pharmacological modulation of key metabolic enzymes including those converting glutamate into &agr;-ketoglutarate (&agr;KG) (and beyond) and acetate into acetyl-coenzyme A (CoA). SummaryOxidative decarboxylation and reductive carboxylation of &agr;KG represent two options for the glutamine metabolism. The canonical forward mode of the TCA cycle fuelled by glutamine may benefit from the decarboxylation of malate into pyruvate for fueling pyruvate dehydrogenase and generating acetyl-CoA to offer a self-sustainable TCA cycle. Under hypoxia and mutations in the TCA cycle, the reductive carboxylation of glutamine-derived &agr;KG into citrate mainly supports lipogenesis via the ATP citrate lyase that cleaves citrate into oxaloacetate and acetyl-CoA. Still, a largely unsuspected source of acetyl-CoA was shown to derive from the direct ligation of acetate to CoA by acetyl-CoA synthetases. Altogether, these findings identify critical metabolic nodes in the glutamine and acetate metabolism as new determinants of tumor metabolic plasticity that may facilitate the design of synthetic lethal treatments.