School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332.
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332.
Proc Natl Acad Sci U S A. 2022 Jan 4;119(1). doi: 10.1073/pnas.2023328119.
Cu/Zn superoxide dismutase (Sod1) is a highly conserved and abundant antioxidant enzyme that detoxifies superoxide (O) by catalyzing its conversion to dioxygen (O) and hydrogen peroxide (HO). Using and mammalian cells, we discovered that a major aspect of the antioxidant function of Sod1 is to integrate O availability to promote NADPH production. The mechanism involves Sod1-derived HO 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 via O 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 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 HO is important for antioxidant defense and a master regulator of metabolism and the thiol redoxome.
铜/锌超氧化物歧化酶（Sod1）是一种高度保守且丰富的抗氧化酶，通过催化超氧化物（O）转化为氧气（O）和过氧化氢（HO）来解毒超氧化物。我们利用酵母和哺乳动物细胞发现，Sod1 的抗氧化功能的一个主要方面是整合 O 的可用性以促进 NADPH 的产生。该机制涉及 Sod1 衍生的 HO 氧化失活糖酵解酶 GAPDH，从而将碳水化合物通量重新路由到戊糖磷酸途径（oxPPP）的氧化阶段，以生成 NADPH。GAPDH 的需氧氧化依赖于 Sod1 并受其限速。因此，Sod1 通过 O 来感知 O，以通过控制 GAPDH 活性来平衡糖酵解和 oxPPP 通量，从而适应空气中的生活。重要的是，这种 Sod1 抗氧化活性的机制需要大部分细胞内的 Sod1，这与 Sod1 对抗 O 毒性的作用不同，后者仅需要总 Sod1 的 <1%。通过质谱分析，我们鉴定了 Sod1 依赖性氧化还原信号的蛋白质组广泛靶标，包括许多代谢酶。总的来说，Sod1 衍生的 HO 对抗氧化防御和代谢以及硫醇氧化还原组的主调控很重要。
