蛋白质修复
中文名称
通路描述
活性氧（ROS）如过氧化氢、超氧阴离子和羟基自由基与细胞内的分子相互作用，导致损伤并损害细胞功能。尽管细胞拥有机制来消除ROS并修复其造成的损伤，但ROS被认为是与年龄相关疾病和衰老过程密切相关的主要因素（Zhang & Weissbach 2008, Kim et al. 2014）。ROS 清除系统包括过氧化物酶、超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶等酶，它们有助于最小化潜在损伤。ROS 反应还可以引起氨基酸侧链的特异性修饰，导致蛋白质/酶的结构改变。甲硫氨酸（Met）和半胱氨酸（Cys）可通过 ROS 氧化为亚磺酸和进一步氧化为磺酸衍生物。游离 Met 和基于蛋白质的 Met 均可被氧化形成甲硫氨酸亚磺酸（MetO）（Brot & Weissbach 1991）。许多蛋白质已被证明会经历此类氧化，从而导致功能改变（Levine et al. 2000）。亚磺酸的形成可以通过甲硫氨酸亚磺酸还原酶系统（MSR）逆转，该系统催化 MetO 还原为 Met（Brot et al. 1981）。该修复过程消耗一个 ROS 当量，因此 MSR 蛋白可作为催化抗氧化剂，去除 ROS（Levine et al. 1996）。甲硫氨酸氧化产生甲硫氨酸的（S）-S-和（R）-S-异构体，它们是异构体，分别由 MSRA 和 MSRB 还原。MSRA 可还原游离和基于蛋白质的甲硫氨酸-(S)-S-氧化物，而 MSRB 专一性地针对基于蛋白质的甲硫氨酸-(R)-S-氧化物。哺乳动物通常只编码一个 MSR 基因，但至少有三个基因编码 MSRB 基因（Hansel et al. 2005）。尽管结构不同，MRSA 和 MRSB 共享共同的三步催化机制。在第一步中，MSR 催化半胱氨酸残基与 MetO 底物相互作用，导致产物释放和形成半胱氨酸亚磺酸。在第二步中，催化半胱氨酸和再生半胱氨酸之间形成分子内二硫键。在第三步中，二硫键由电子供体，即 NADPH 依赖的硫蛋白/TR 系统，还原，导致 MSR 活性位点的再生（Boschi-Muller et al. 2008）。
英文描述
Citric acid cycle (TCA cycle) In the citric acid or tricarboxylic acid (TCA) cycle, the acetyl group of acetyl CoA (derived primarily from oxidative decarboxylation of pyruvate, beta-oxidation of long-chain fatty acids, and catabolism of ketone bodies and several amino acids) can be completely oxidized to CO2 in reactions that also yield one high-energy phosphate bond (as GTP or ATP) and four reducing equivalents (three NADH + H+, and one FADH2). Then, the electron transport chain oxidizes NADH and FADH2 to yield nine more high-energy phosphate bonds (as ATP). All reactions of the citric acid cycle take place in the mitochondrion.Eight canonical reactions mediate the synthesis of citrate from acetyl-CoA and oxaloacetate and the metabolism of citrate to re-form oxaloacetate. Three reactions are reversible: the interconversions of citrate and isocitrate, of fumarate and malate, and of malate and oxaloacetate. The reverse reactions are irrelevant under normal physiological conditions but appear to have a role in glucose- and glutamine-stimulated insulin secretion (Zhang et al., 2020) and cancer metabolism (e.g., Jiang et al., 2016). Succinate synthesis from succinyl-CoA can be coupled to the phosphorylation of either GDP (the canonical reaction) or ADP; we annotate both reactions. Two mitochondrial isocitrate dehydrogenase isozymes catalyze the oxidative decarboxylation of isocitrate to form alpha-ketoglutarate (2-oxoglutarate): IDH3 catalyzes the canonical reaction coupled to the reduction of NAD+, while IDH2 catalyzes the same reaction coupled to the reduction of NADP+, a reaction whose normal physiological function is unclear. Both reactions are annotated.The cyclical nature of the reactions responsible for the oxidation of acetate was first suggested by Hans Krebs from biochemical studies of pigeon breast muscle (Krebs et al., 1938; Krebs and Eggleston, 1940). Ochoa and colleagues studied many molecular details of individual reactions, mainly by studying enzymes purified from pig hearts (Ochoa, 1980). While the human homologs of these enzymes have all been identified, their biochemical characterization has, in general, been limited, and many molecular details of the human reactions are inferred from those worked out in studies of the model systems. Studies examining the impact of elevated citric acid cycle intermediates such as succinate and fumarate led to the recognition of the role of metabolites in driving cancer progression ('oncometabolites') (Pollard et al., 2005; reviewed in Hayashi et al., 2018). The role of TCA enzymes in disease was reviewed by Kang et al., 2021.
所含基因
17 个基因