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标题：Sod1 integrates oxygen availability to redox regulate NADPH production and the thiol redoxome
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作者：Claudia Montllor-Albalate ; Hyojung Kim ; Anna E. Thompson 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：1
DOI：10.1073/pnas.2023328119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Cu/Zn superoxide dismutase (Sod1) is a key antioxidant enzyme, and its importance is underscored by the fact that its ablation in cell and animal models results in oxidative stress; metabolic defects; and reductions in cell proliferation, viability, and lifespan. Curiously, Sod1 detoxifies superoxide radicals (O 2 •−) in a manner that produces an oxidant as byproduct, hydrogen peroxide (H 2O 2). While much is known about the necessity of scavenging O 2 •−, it is less clear what the physiological roles of Sod1-derived H 2O 2 are. We discovered that Sod1-derived H 2O 2 plays an important role in antioxidant defense by stimulating the production of NADPH, a vital cellular reductant required for reactive oxygen species scavenging enzymes, as well as redox regulating a large network of enzymes. Cu/Zn superoxide dismutase (Sod1) is a highly conserved and abundant antioxidant enzyme that detoxifies superoxide (O 2 •−) by catalyzing its conversion to dioxygen (O 2) and hydrogen peroxide (H 2O 2). Using Saccharomyces cerevisiae and mammalian cells, we discovered that a major aspect of the antioxidant function of Sod1 is to integrate O 2 availability to promote NADPH production. The mechanism involves Sod1-derived H 2O 2 oxidatively inactivating the glycolytic enzyme, GAPDH, which in turn reroutes carbohydrate flux to the oxidative phase of the pentose phosphate pathway (oxPPP) to generate NADPH. The aerobic oxidation of GAPDH is dependent on and rate-limited by Sod1. Thus, Sod1 senses O 2 via O 2 •− to balance glycolytic and oxPPP flux, through control of GAPDH activity, for adaptation to life in air. Importantly, this mechanism for Sod1 antioxidant activity requires the bulk of cellular Sod1, unlike for its role in protection against O 2 •− toxicity, which only requires <1% of total Sod1. Using mass spectrometry, we identified proteome-wide targets of Sod1-dependent redox signaling, including numerous metabolic enzymes. Altogether, Sod1-derived H 2O 2 is important for antioxidant defense and a master regulator of metabolism and the thiol redoxome.
关键词：enoxygen sensingsuperoxide dismutaseredox signalingglycolysispentose phosphate pathway