title: An inhibitor of protein arginine methyltransferases, 7,7'-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1), is a potent scavenger of NADPH-oxidase-derived superoxide.
abstract: The methylation of proteins is an important post-translational mechanism that has been established to influence the activity of nuclear and nucleic acid binding proteins. Much less is known about the importance of protein methylation in the regulation of cytosolic proteins. Increased methylation of proteins is observed in cardiovascular disease and occurs in conjunction with elevated production of reactive oxygen species. However, the nature of the relationship between reactive oxygen species and protein methylation is poorly understood. Therefore, the goal of the current study was to determine whether protein methylation influences the catalytic activity of the NADPH oxidases (Nox), which are a family of enzymes responsible for the generation of superoxide. We found that the selective inhibitor of protein arginine methyltransferases 7,7'-carbonylbis(azanediyl)bis(4-hydroxynaphthalene-2-sulfonic acid (AMI-1) was a potent antagonist of Nox-derived superoxide production. However, structurally and mechanistically dissimilar inhibitors of protein methylation and coexpression of protein arginine methyltransferase 1 did not influence Nox activity. Rather, the effect of AMI-1 was rapidly reversible and could be demonstrated in an assay using chemically synthesized superoxide. We conclude that protein methylation does not regulate the activity of NADPH-oxidases and that AMI-1 is a potent antioxidant with a greater potency than 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron) and 4-hydroxy-2,2,6,6-tetramethylpiperydine-1-oxyl (Tempol).
authors.affiliation: Department of Pharmacology, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: David J R
authors.initials: DJ
authors.lastname: Fulton
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009282:Naphthalenesulfonates / Q000494:pharmacology*; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C535077:7,7'-carbonylbis(azanediyl) bis(4-hydroxynaphthalene-2-sulfonic acid; D000975:Antioxidants; D016166:Free Radical Scavengers; D009282:Naphthalenesulfonates; D013481:Superoxides; D014508:Urea; D019255:NADPH Oxidases; D011484:Protein-Arginine N-Methyltransferases