Natarajan Sathish Kumar, Becker Donald F
Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE.
Cell Health Cytoskelet. 2012 Feb 1;2012(4):11-27. doi: 10.2147/CHC.S4955.
Flavoproteins catalyze a variety of reactions utilizing flavin mononucleotide or flavin adenine dinucleotide as cofactors. The oxidoreductase properties of flavoenzymes implicate them in redox homeostasis, oxidative stress, and various cellular processes, including programmed cell death. Here we explore three critical flavoproteins involved in apoptosis and redox signaling, ie, apoptosis-inducing factor (AIF), proline dehydrogenase, and NADPH oxidase. These proteins have diverse biochemical functions and influence apoptotic signaling by unique mechanisms. The role of AIF in apoptotic signaling is two-fold, with AIF changing intracellular location from the inner mitochondrial membrane space to the nucleus upon exposure of cells to apoptotic stimuli. In the mitochondria, AIF enhances mitochondrial bioenergetics and complex I activity/assembly to help maintain proper cellular redox homeostasis. After translocating to the nucleus, AIF forms a chromatin degrading complex with other proteins, such as cyclophilin A. AIF translocation from the mitochondria to the nucleus is triggered by oxidative stress, implicating AIF as a mitochondrial redox sensor. Proline dehydrogenase is a membrane-associated flavoenzyme in the mitochondrion that catalyzes the rate-limiting step of proline oxidation. Upregulation of proline dehydrogenase by the tumor suppressor, p53, leads to enhanced mitochondrial reactive oxygen species that induce the intrinsic apoptotic pathway. NADPH oxidases are a group of enzymes that generate reactive oxygen species for oxidative stress and signaling purposes. Upon activation, NADPH oxidase 2 generates a burst of superoxide in neutrophils that leads to killing of microbes during phagocytosis. NADPH oxidases also participate in redox signaling that involves hydrogen peroxide-mediated activation of different pathways regulating cell proliferation and cell death. Potential therapeutic strategies for each enzyme are also highlighted.
黄素蛋白利用黄素单核苷酸或黄素腺嘌呤二核苷酸作为辅因子催化多种反应。黄素酶的氧化还原酶特性使其参与氧化还原稳态、氧化应激以及包括程序性细胞死亡在内的各种细胞过程。在此，我们探讨参与细胞凋亡和氧化还原信号传导的三种关键黄素蛋白，即凋亡诱导因子（AIF）、脯氨酸脱氢酶和NADPH氧化酶。这些蛋白质具有多种生化功能，并通过独特机制影响凋亡信号传导。AIF在凋亡信号传导中的作用具有双重性，在细胞受到凋亡刺激时，AIF的细胞内定位从线粒体内膜间隙转变至细胞核。在线粒体中，AIF增强线粒体生物能量代谢以及复合体I的活性/组装，以帮助维持适当的细胞氧化还原稳态。转位至细胞核后，AIF与其他蛋白质（如亲环蛋白A）形成一种染色质降解复合体。AIF从线粒体向细胞核的转位由氧化应激触发，这表明AIF是一种线粒体氧化还原传感器。脯氨酸脱氢酶是线粒体中一种与膜相关的黄素酶，催化脯氨酸氧化的限速步骤。肿瘤抑制因子p53对脯氨酸脱氢酶的上调导致线粒体活性氧增加，从而诱导内源性凋亡途径。NADPH氧化酶是一类为氧化应激和信号传导目的而产生活性氧的酶。激活后，NADPH氧化酶2在中性粒细胞中产生一阵超氧化物，导致吞噬作用期间微生物的杀伤。NADPH氧化酶还参与氧化还原信号传导，该信号传导涉及过氧化氢介导的对调节细胞增殖和细胞死亡的不同途径的激活。还强调了针对每种酶的潜在治疗策略。
