Effects of nitric oxide and nitric oxide-derived species on prostaglandin endoperoxide synthase and prostaglandin biosynthesis

Prostaglandins and NO. are important mediators of inflammation and other ph ysiological and pathophysiological processes. Continuous production of thes e molecules in chronic inflammatory conditions has been linked to developme nt of autoimmune disorders, coronary artery disease, and cancer. There is m ounting evidence for a biological relationship between prostanoid biosynthe sis and NO biosynthesis, Upon stimulation, many cells express high levels o f nitric oxide synthase (NOS) and prostaglandin endoperoxide synthase (PGHS ), There are reports of stimulation of prostaglandin biosynthesis in these cells by direct interaction between NO. and PGHS, but this is not universal ly observed. Clarification of the role of NO. in PGHS catalysis has been at tempted by examining NO. interactions with purified PGHS, including binding to its heme prosthetic group, cysteines, and tyrosyl radicals, However, a clear picture of the mechanism of PGHS stimulation by NO. has not yet emerg ed. Available studies suggest that NO. may only be a precursor to the molec ule that interacts with PGHS, Peroxynitrite (from O-2(.-)+NO.) reacts direc tly with PGHS to activate prostaglandin synthesis. Furthermore, removal of O-2(.-) from RAW 267.4 cells that produce NO. and PGHS inhibits prostagland in biosynthesis to the same extent as NOS inhibitors. This interaction betw een reactive nitrogen species and PGHS may provide new approaches to the co ntrol of inflammation in acute and chronic settings.