CO regulates directional biotransformation of glucose via protein arginine methylation.

一氧化碳（CO）是一种多功能气体介质，可调节平滑肌张力、神经传递、细胞内代谢、细胞凋亡和增殖。由于代谢系统中具有金属中心辅基的大分子（如酶）可能作为分子氧或CO共价结合的靶点，本文利用稳定同位素^C_6标记的葡萄糖，通过代谢组学通量分析，即CO抑制糖酵解通量，提供了CO调控葡萄糖定向生物转化的证据<13>，而在人单核细胞系U937中通过蛋白甲基化增加进入磷酸戊糖途径（PPP）的流量。此外，我们发现糖酵解促进酶6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶，异构体3（PFKFB 3），负责生产果糖-2，6-二磷酸（F-2，6-BP），被蛋白质精氨酸甲基转移酶1（PRMT 1）甲基化。一氧化碳可引起PFKFB 3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激活流向PPP，随后增加NADPH，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起重要作用。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转换）对抗氧化应激而发挥细胞保护作用。

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.