title: Emerging regulatory paradigms in glutathione metabolism.
abstract: One of the hallmarks of cancer is the ability to generate and withstand unusual levels of oxidative stress. In part, this property of tumor cells is conferred by elevation of the cellular redox buffer glutathione. Though enzymes of the glutathione synthesis and salvage pathways have been characterized for several decades, we still lack a comprehensive understanding of their independent and coordinate regulatory mechanisms. Recent studies have further revealed that overall central metabolic pathways are frequently altered in various tumor types, resulting in significant increases in biosynthetic capacity and feeding into glutathione synthesis. In this review, we will discuss the enzymes and pathways affecting glutathione flux in cancer and summarize current models for regulating cellular glutathione through both de novo synthesis and efficient salvage. In addition, we examine the integration of glutathione metabolism with other altered fates of intermediary metabolites and highlight remaining questions about molecular details of the accepted regulatory modes.
authors: Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska, USA.
authors: Yilin
authors: Y
authors: Liu
authors: Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska, USA.
authors: Annastasia S
authors: AS
authors: Hyde
authors: Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska, USA.
authors: Melanie A
authors: MA
authors: Simpson
authors: Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska, USA. Electronic address: jbarycki2@unl.edu.
authors: Joseph J
authors: JJ
authors: Barycki
mesh_terms: D000818:Animals; D002021:Buffers; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism*; D005981:Glutathione Synthase / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008055:Lipids / Q000737:chemistry; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D011752:Pyroglutamate Hydrolase / Q000378:metabolism; D005722:gamma-Glutamylcyclotransferase / Q000378:metabolism
chemical_list: D002021:Buffers; D008055:Lipids; D011752:Pyroglutamate Hydrolase; D005722:gamma-Glutamylcyclotransferase; D005981:Glutathione Synthase; D005978:Glutathione
keywords: 5-Oxoprolinase; ChaC1; Glutamate cysteine ligase; Glutathione; Glutathione synthetase; Redox homeostasis; γ-Glutamyl cycle; γ-Glutamylcyclotransferase; γ-Glutamyltranspeptidase