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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)是一种多功能的气体介质，可调节肌张力、神经传递、细胞内代谢、细胞凋亡和细胞增殖。由于具有金属中心基团的大分子，如代谢系统中的酶，可能成为分子氧或CO共价结合的靶标。在这里，我们通过稳定同位素13&gt；C_6标记葡萄糖的代谢组通量分析，提供了CO调节葡萄糖定向生物转化的证据，即CO抑制进入糖酵解的通量，而通过蛋白质甲基化增加进入磷酸戊糖途径(PPP)的通量。此外，我们还发现糖酵解促进酶6-磷酸果糖-2-激酶/果糖-2，6-二磷酸异构体3(PFKFB3)是产生2，6-二磷酸果糖(F-2，6-BP)的负责酶，它被蛋白质精氨酸甲基转移酶1(PRMT1)甲基化。CO可导致PFKFB3去甲基化，降低细胞内F-2，6-BP水平，从而抑制糖酵解。因此，CO激活了进入PPP的通量，继而增加了NADPH，NADPH是主要用于还原谷胱甘肽的必需还原辅因子，因此PPP在保护氧化应激诱导的细胞凋亡中发挥着重要作用。因此，应激诱导的CO通过调节葡萄糖利用的代谢转变(糖酵解-PPP转变)来对抗氧化应激，从而发挥细胞保护作用。