CO regulates directional biotransformation of glucose via protein arginine methylation.

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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.