CO regulates directional biotransformation of glucose via protein arginine methylation.

CO 通过蛋白质精氨酸甲基化调节葡萄糖的定向生物转化。

基本信息

批准号：
22710222
负责人：
YAMAMOTO Takehiro
金额：
$ 2.5万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2011
项目状态：
已结题

项目摘要

Carbon monoxide(CO) is a multifunctional gaseous mediators to regulate smooth muscle tonus, neurotransmission, intracellular metabolism, apoptosis, and proliferation. Since macromolecules possessing metal-centered prosthetic groups such as enzymes in metabolic systems might serve as targets for covalent binding of molecular oxygen or CO. Here, we provide the evidences that CO regulates directional biotransformation of glucose by metabolome flux analysis using stable isotope,^<13> C_6-labeled glucose, that is, CO suppress the flux into glycolysis, while increase the flux into pentose phosphate pathway(PPP) via protein methylation in human monoblastic cell line U937. Furthermore, we showed that glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform3(PFKFB3), responsible enzyme for the production of fructose-2, 6-bisphosphate(F-2, 6-BP), was methylated by protein arginine methyltransferase 1(PRMT1). Administration of CO caused the demethylation of PFKFB3 and decreased the intracellular F-2, 6-BP level, leading to inhibition of glycolysis. As a result, CO activates the flux into PPP, followed by the augmentation of NADPH, essential reducing cofactor mainly used for reduction of glutathione, hence PPP plays an important role in protection from oxidative stress-induced apoptosis. Thus, stress-induced CO acts cytoprotective effect by regulating metabolic shift of glucose utilization(glycolysis-PPP transition) against oxidative stress.

一氧化碳（CO）是一种多功能气态介质，可调节平滑肌托内斯，神经传递，细胞内代谢，凋亡和增殖。由于代谢系统中具有以金属为中心的人类群（例如酶）的大分子可能是分子氧或共同结合的靶标。糖酵解，同时通过人单细胞细胞系U937中的蛋白甲基化将通量通过蛋白甲基化增加到五磷酸途径（PPP）。此外，我们表明，糖酵解促进酶6-磷酸果-2-激酶/果糖-2，6-双磷酸酶，同型3（PFKFB3），负责产生果糖2、6-磷酸磷酸盐（F-2，6-BP）的果糖2、6-BP）的酶是由蛋白质甲基甲基甲基甲基甲基甲基甲基甲基磷酸酯。 CO的给药导致PFKFB3的脱甲基化并降低细胞内F-2，6 bp水平，从而抑制糖酵解。结果，CO将通量激活到PPP中，然后将NADPH的增强激活，这主要还原辅助因子主要用于还原谷胱甘肽，因此PPP在保护氧化应激诱导的凋亡中起着重要作用。因此，应力诱导的CO通过调节葡萄糖利用（糖酵解-PPP过渡）对氧化应激的代谢转移而作用。