近日，中科院上海药物所化学蛋白质组学研究中心与美国芝加哥大学、密歇根大学在一项合作研究中，首次在哺乳动物细胞中对去乙酰化调控酶Sirt5调控的琥珀酰底物进行了系统的蛋白质组学研究，在779个蛋白上鉴定出2500多个琥珀酰位点，并研究揭示了蛋白琥珀酰修饰具有广泛调节细胞代谢的作用，同时也提示此修饰可能影响其他重要细胞生物学功能。相关研究成果日前发表于最新一期的《分子细胞》杂志。
据介绍，蛋白翻译后修饰对蛋白质的结构和功能起着关键作用，是细胞精细调节生理活动的关键之一。因而，蛋白翻译后修饰通路研究是目前新药研发的重要热点之一。
研究人员通过综合运用生物质谱、生物化学和生物信息学方法，证明琥珀酰化广泛存在于线粒体能量代谢调控酶中，参与调控包括三羧酸循环、氨基酸代谢以及脂肪酸代谢在内的多个代谢信号通路。同时，研究人员也发现琥珀酰化存在于细胞浆和细胞核蛋白中，并揭示了琥珀酰化能抑制丙酮酸脱氢酶和琥珀酸脱氢酶复合物活性。（生物谷 Bioon.com）
生物谷推荐的英文摘要
Molecular Cell Doi：10.1016/j.molcel.2013.06.001
SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways
Jeongsoon Park1, 6, Yue Chen3, 6, Daniel X. Tishkoff1, 5, Chao Peng3, Minjia Tan3, 4, Lunzhai Dai3, Zhongyu Xie3, Yi Zhang4, Bernadette M.M. Zwaans1, Mary E. Skinner1, David B. Lombard1, 2, Yingming Zhao
Protein function is regulated by diverse posttranslational modifications. The mitochondrial sirtuin SIRT5 removes malonyl and succinyl moieties from target lysines. The spectrum of protein substrates subject to these modifications is unknown. We report systematic profiling of the mammalian succinylome, identifying 2,565 succinylation sites on 779 proteins. Most of these do not overlap with acetylation sites, suggesting differential regulation of succinylation and acetylation. Our analysis reveals potential impacts of lysine succinylation on enzymes involved in mitochondrial metabolism; e.g., amino acid degradation, the tricarboxylic acid cycle (TCA) cycle, and fatty acid metabolism. Lysine succinylation is also present on cytosolic and nuclear proteins; indeed, we show that a substantial fraction of SIRT5 is extramitochondrial. SIRT5 represses biochemical activity of, and cellular respiration through, two protein complexes identified in our analysis, pyruvate dehydrogenase complex and succinate dehydrogenase. Our data reveal widespread roles for lysine succinylation in regulating metabolism and potentially other cellular functions.
