Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aspartokinase Homoserine Dehydrogenase / genetics
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Aspartokinase Homoserine Dehydrogenase / metabolism*
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Base Sequence
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Drug Resistance, Microbial
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Female
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Glutathione / analogs & derivatives
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Glutathione / pharmacology
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Homocysteine / metabolism
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Homocysteine / pharmacology
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Homocysteine / physiology*
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Mercaptoethanol*
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Mice
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Mice, Inbred C3H
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Microbial Sensitivity Tests
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Molecular Sequence Data
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Mutagenesis, Insertional
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Nitric Oxide / antagonists & inhibitors*
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Nitric Oxide / metabolism
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Nitroso Compounds / pharmacology
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S-Nitrosoglutathione
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S-Nitrosothiols*
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Salmonella Infections, Animal / microbiology
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Salmonella typhimurium / cytology
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Salmonella typhimurium / drug effects
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Salmonella typhimurium / pathogenicity
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Salmonella typhimurium / physiology*
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Virulence
Substances
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Nitroso Compounds
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S-Nitrosothiols
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Homocysteine
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Nitric Oxide
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S-Nitrosoglutathione
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Mercaptoethanol
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S-nitrosomercaptoethanol
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Aspartokinase Homoserine Dehydrogenase
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Glutathione