蛋白翻譯后修飾對蛋白質(zhì)的結(jié)構(gòu)和功能起著關(guān)鍵作用,，是細(xì)胞精細(xì)調(diào)節(jié)生理活動的關(guān)鍵之一。因而,，蛋白翻譯后修飾通路研究是目前新藥研發(fā)的重要熱點之一,。
中科院上海藥物研究所化學(xué)蛋白質(zhì)組學(xué)研究中心與美國芝加哥大學(xué)、密西根大學(xué)合作研究,，首次在哺乳動物細(xì)胞中對去乙?；{(diào)控酶Sirt5調(diào)控的琥珀酰底物進行了系統(tǒng)的蛋白質(zhì)組學(xué)研究，在779個蛋白上鑒定出2500多個琥珀酰位點,。此項研究通過綜合運用生物質(zhì)譜、生物化學(xué)和生物信息學(xué)方法,，證明琥珀?；瘡V泛存在于線粒體能量代謝調(diào)控酶中，參與調(diào)控包括三羧酸循環(huán),、氨基酸代謝以及脂肪酸代謝在內(nèi)的多個代謝信號通路,。同時也發(fā)現(xiàn)，琥珀?；嬖谟诩?xì)胞漿和細(xì)胞核蛋白中,，并揭示了琥珀酰化能抑制丙酮酸脫氫酶和琥珀酸脫氫酶復(fù)合物活性,。此項研究揭示了蛋白琥珀酰修飾具有廣泛調(diào)節(jié)細(xì)胞代謝的作用,，同時也提示此修飾可能影響其它重要細(xì)胞生物學(xué)功能。
這是化學(xué)蛋白質(zhì)組學(xué)研究中心繼首次發(fā)現(xiàn)賴氨酸去琥珀酰和去丙二酰兩種新翻譯后修飾通路,，并首次揭示去乙?；窼irt5實為賴氨酸去琥珀酰和丙二酰化的調(diào)控酶之后的又一重要研究突破,。首次系統(tǒng)性揭示了受賴氨酸去乙?；福℉DACs）Sirt5調(diào)控的琥珀酰化底物蛋白,，發(fā)現(xiàn)了琥珀?；揎棇δ芰看x中的關(guān)鍵酶的調(diào)控作用，進一步明確了Sirt5的去琥珀?；饔玫纳飳W(xué)意義,，并為Sirt5的生物學(xué)和新藥研究提供了重要資源。
相關(guān)研究工作上海藥物所以共同通訊作者單位于6月27日發(fā)表在最新一期的國際期刊Molecular Cell雜志上,。（生物谷Bioon.com）
doi:10.1016/j.molcel.2013.06.001
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SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways
Jeongsoon Park, Yue Chen, Daniel X. Tishkoff, Chao Peng, Minjia Tan, Lunzhai Dai, Zhongyu Xie, Yi Zhang, Bernadette M.M. Zwaans, Mary E. Skinner, David B. Lombard, 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.
