從復(fù)旦大學(xué)獲悉，該校生物醫(yī)學(xué)研究院趙世民教授領(lǐng)銜的研究團(tuán)隊(duì)發(fā)現(xiàn),，通過(guò)調(diào)節(jié)人體內(nèi)一種名叫“PEPCK1”的代謝酶可有效控制葡萄糖濃度,。該項(xiàng)成果為糖尿病干預(yù)與治療帶來(lái)新的希望，并于9日刊登在國(guó)際學(xué)術(shù)期刊《分子細(xì)胞》（Molecular Cell）雜志上,。
趙世民介紹,，科學(xué)家把人體內(nèi)氨基酸等非葡萄糖營(yíng)養(yǎng)物質(zhì)轉(zhuǎn)化為葡萄糖的過(guò)程叫做“糖異生”。正常情況下,，人體會(huì)根據(jù)需要自動(dòng)轉(zhuǎn)換葡萄糖,，而PEPCK1是控制人體細(xì)胞糖異生過(guò)程的關(guān)鍵酶。
“PEPCK1的重要任務(wù)是,，通過(guò)‘糖異生’通路將其他能量物質(zhì)轉(zhuǎn)化為葡萄糖,，但是，如果PEPCK1的活性過(guò)高將會(huì)導(dǎo)致血液中葡萄糖的濃度上升而誘發(fā)糖尿病,。因此嚴(yán)格調(diào)控PEPCK1的活性是控制糖尿病的有效手段,。”
趙世民及其研究團(tuán)隊(duì)的研究成果表明：當(dāng)“被修飾化”的PEPCK1被細(xì)胞內(nèi)的蛋白酶體降解時(shí)，其蛋白濃度降低會(huì)抑制“糖異生通路”的發(fā)生,，從而使人體內(nèi)葡萄糖濃度降低,，有效控制糖尿病的發(fā)生和發(fā)展。
而PEPCK1“被修飾化”的前提,，則是PEPCK1被乙?；阴；潭仁艿狡咸烟菨舛鹊恼{(diào)控,，當(dāng)葡萄糖濃度較高時(shí),，乙酰化后的PEPCK1會(huì)結(jié)合人體內(nèi)一種叫UBR5的泛素鏈接酶,，從而使自己“被修飾化”,。
據(jù)悉，上述研究不僅闡明了PEPCK1活性的分子調(diào)控機(jī)理,，而且發(fā)現(xiàn)了人體內(nèi)與PEPCK1相關(guān)的乙?；?、去乙?；负头核劓溄用傅闹匾δ埽@一系列酶均可作為未來(lái)調(diào)節(jié)糖異生通路的藥物蛋白靶標(biāo),。也就是說(shuō),，今后科學(xué)家可以通過(guò)藥物改變?nèi)梭w內(nèi)這一系列酶的活性來(lái)控制血液葡萄糖濃度的高低，進(jìn)而有效防治糖尿病,。（生物谷Bioon.com）
生物谷推薦原味出處：
Molecular Cell DOI:10.1016/j.molcel.2011.04.028
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
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.
