Homocysteine antagonism of nitric oxide-related cytostasis in Salmonella typhimurium.
Nitric oxide (NO) is associated with broad-spectrum antimicrobial activity of particular importance in infections caused by intracellular pathogens. An insertion mutation in the metL gene of Salmonella typhimurium conferred specific hypersusceptibility to S-nitrosothiol NO-donor compounds and attenuated virulence of the organism in mice. The metL gene product catalyzes two proximal metabolic steps required for homocysteine biosynthesis. S-Nitrosothiol resistance was restored by exogenous homocysteine or introduction of the metL gene on a plasmid. Measurement of expression of the homocysteine-sensitive metH gene indicated that S-nitrosothiols may directly deplete intracellular homocysteine. Homocysteine may act as an endogenous NO antagonist in diverse processes including infection, atherosclerosis, and neurologic disease.
De Groote
M A
MA
Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Testerman
T
T
Xu
Y
Y
Stauffer
G
G
Fang
F C
FC
D000818:Animals; D001225:Aspartokinase Homoserine Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D004352:Drug Resistance, Microbial; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006710:Homocysteine / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008623:Mercaptoethanol; D051379:Mice; D008809:Mice, Inbred C3H; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D026422:S-Nitrosoglutathione; D026403:S-Nitrosothiols; D012481:Salmonella Infections, Animal / Q000382:microbiology; D012486:Salmonella typhimurium / Q000166:cytology / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D014774:Virulence
D009603:Nitroso Compounds; D026403:S-Nitrosothiols; D006710:Homocysteine; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; D001225:Aspartokinase Homoserine Dehydrogenase; D005978:Glutathione