Regulation of redox signaling involving chemical conjugation of protein thiols by nitric oxide and electrophiles.
Nitric oxide (NO), a gaseous free radical that is biologically synthesized by nitric oxide synthases, participates in a critical fashion in the regulation of diverse physiological functions including vascular and neuronal signal transduction, host defense, and cell death regulation. This article reviews the chemical and biochemical mechanisms of protein thiol modifications caused by NO and by electrophiles derived from NO metabolism. The classical NO signaling pathway involves formation of the second messenger guanosine 3',5'-cyclic monophosphate (cGMP). Post-translational modifications of redox-sensitive protein thiols have also been shown to be important in this signaling pathway. For instance, redox-sensitive thiols are targets for NO conjugation and formation of S-nitrosothiols. Electrophiles generated by reactions of NO or reactive nitrogen oxide species and biomolecules (i.e., fatty acids) effect thiol conjugations through S-alkylation. Among this class of reactions, S-guanylation is particularly emphasized. S-Guanylation is a novel type of S-alkylation with nitrated cGMP that contributes to the cytoprotective effects of NO. Post-translational modifications of thiols affect protein structures and functions: allosteric effects may alter protein structure, modification of active centers of enzymes may suppress enzyme actions, and modifications may modulate protein-protein interactions. Better understanding of protein modification by NO-derived electrophiles and the molecular basis of NO signaling would be useful in the development of new diagnostic methods and treatment of diseases related to NO metabolism.
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Tomohiro
T
Sawa
Hirokazu
H
Arimoto
Takaaki
T
Akaike
D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism*
D005227:Fatty Acids; D011506:Proteins; D026361:Reactive Nitrogen Species; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide