Inactivation of the inducible nitric oxide synthase by peroxynitrite

Chemical Research in Toxicology
A F HühmerC Schöneich

Abstract

The simultaneous production of superoxide and nitric oxide by stimulated human neutrophils leads to the formation of peroxynitrite, a physiologically important bactericidal agent. We have investigated two possible pathways for the inactivation of inducible nitric oxide synthase (NOS-II) by peroxynitrite: inactivation of NOS-II through oxidation of the tightly bound cofactor calmodulin (CaM) and direct interaction of ONOO-/ONOOH with the NOS-II protein. Studies of two model peptides indicated that the Ca2+-dependent binding to CaM of a typical high-affinity sequence, melittin, significantly prevented Met oxidation in CaM by ONOO-/ONOOH. In contrast, binding of the putative CaM-binding domain of human hepatocyte NOS-II (NOS-II509-534) to CaM only marginally prevented the oxidation of Met residues in CaM. When the native NOS-II/CaM complex was exposed to peroxynitrite, CaM was inert toward oxidation. Nevertheless, even small amounts of peroxynitrite abolished the activity of NOS-II through direct interaction with the heme. The loss of activity was paralleled by a decrease in heme absorbance and a shift of the absorbance maximum from 419 to 409 nm. The presence of the cofactor tetrahydrobiopterin during peroxynitrite exposure did n...Continue Reading

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