HOMOCYSTEINE ANTAGONISM OF NITRIC OXIDE-RELATED CYTOSTASIS IN SALMONELLA-TYPHIMURIUM

Nitric oxide (NO) is associated with broad-spectrum antimicrobial acti vity of particular importance in infections caused by intracellular pa thogens. An insertion mutation in the metL gene of Salmonella typhimur ium conferred specific hypersusceptibility to S-nitrosothiol NO-donor compounds and attenuated virulence of the organism in mice. The metL g ene product catalyzes two proximal metabolic steps required for homocy steine biosynthesis. S-Nitrosothiol resistance was restored by exogeno us homocysteine or introduction of the metL gene on a plasmid. Measure ment of expression of the homocysteine-sensitive metH gene indicated t hat S-nitrosothiols may directly deplete intracellular homocysteine. H omocysteine may act as an endogenous NO antagonist in diverse processe s including infection, atherosclerosis, and neurologic disease.