Molecular Cell-调节人体内一种代谢酶可有效控制葡萄糖浓度
Molecular Cell：调节人体内一种代谢酶可有效控制葡萄糖浓度
2011/07/12 14:10:57
从复旦大学获悉，该校生物医学研究院赵世民教授领衔的研究团队发现，通过调节人体内一种名叫“PEPCK1”的代谢酶可有效控制葡萄糖浓度。该项成果为糖尿病干预与治疗带来新的希望，并于9日刊登在国际学术期刊《分子细胞》（Molecular Cell）杂志上。
赵世民介绍，科学家把人体内氨基酸等非葡萄糖营养物质转化为葡萄糖的过程叫做“糖异生”。正常情况下，人体会根据需要自动转换葡萄糖，而PEPCK1是控制人体细胞糖异生过程的关键酶。
“PEPCK1的重要任务是，通过‘糖异生’通路将其他能量物质转化为葡萄糖，但是，如果PEPCK1的活性过高将会导致血液中葡萄糖的浓度上升而诱发糖尿病。因此严格调控PEPCK1的活性是控制糖尿病的有效手段。”
赵世民及其研究团队的研究成果表明：当“被修饰化”的PEPCK1被细胞内的蛋白酶体降解时，其蛋白浓度降低会抑制“糖异生通路”的发生，从而使人体内葡萄糖浓度降低，有效控制糖尿病的发生和发展。
而PEPCK1“被修饰化”的前提，则是PEPCK1被乙酰化，乙酰化程度受到葡萄糖浓度的调控，当葡萄糖浓度较高时，乙酰化后的PEPCK1会结合人体内一种叫UBR5的泛素链接酶，从而使自己“被修饰化”。
据悉，上述研究不仅阐明了PEPCK1活性的分子调控机理，而且发现了人体内与PEPCK1相关的乙酰化酶、去乙酰化酶和泛素链接酶的重要功能，这一系列酶均可作为未来调节糖异生通路的药物蛋白靶标。也就是说，今后科学家可以通过药物改变人体内这一系列酶的活性来控制血液葡萄糖浓度的高低，进而有效防治糖尿病。
Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase
Wenqing Jiang, Shiwen Wang, Mengtao Xiao, Yan Lin, Lisha Zhou, Qunying Lei, Yue Xiong, Kun-Liang Guan, Shimin Zhao
Molecular Cell, DOI:10.1016/j.molcel.2011.04.028
Protein acetylation has emerged as a major mechanism in regulating cellular metabolism. Whereas most glycolytic steps are reversible, the reaction catalyzed by pyruvate kinase is irreversible, and the reverse reaction requires phosphoenolpyruvate carboxykinase (PEPCK1) to commit for gluconeogenesis. Here, we show that acetylation regulates the stability of the gluconeogenic rate-limiting enzyme PEPCK1, thereby modulating cellular response to glucose. High glucose destabilizes PEPCK1 by stimulating its acetylation. PEPCK1 is acetylated by the P300 acetyltransferase, and this acetylation stimulates the interaction between PEPCK1 and UBR5, a HECT domain containing E3 ubiquitin ligase, therefore promoting PEPCK1 ubiquitinylation and degradation. Conversely, SIRT2 deacetylates and stabilizes PEPCK1. These observations represent an example that acetylation targets a metabolic enzyme to a specific E3 ligase in response to metabolic condition changes. Given that increased levels of PEPCK are linked with type II diabetes, this study also identifies potential therapeutic targets for diabetes.