title: Low-molecular-weight thiol-dependent antioxidant and antinitrosative defences in Salmonella pathogenesis.
abstract: We found herein that the intracytoplasmic pool of the low-molecular-weight (LMW) thiol glutathione (GSH) is readily oxidized in Salmonella exposed to nitric oxide (NO). The hypersusceptibility of gshA and gshB mutants lacking γ-glutamylcysteine and glutathione synthetases to NO and S-nitrosoglutathione indicates that GSH antagonizes the bacteriostatic activity of reactive nitrogen species. Metabolites of the GSH biosynthetic pathway do not affect the enzymatic activity of classical NO targets such as quinol oxidases. In contrast, LMW thiols diminish the nitrosative stress experienced by enzymes, such as glutamine oxoglutarate amidotransferase, that contain redox active cysteines. LMW thiols also preserve the transcription of Salmonella pathogenicity island 2 gene targets from the inhibitory activity of nitrogen oxides. These findings are consistent with the idea that GSH scavenges reactive nitrogen species (RNS) other than NO. Compared with the adaptive response afforded by inducible systems such as the hmp-encoded flavohaemoprotein, gshA, encoding the first step of GSH biosynthesis, is constitutively expressed in Salmonella. An acute model of salmonellosis has revealed that the antioxidant and antinitrosative properties associated with the GSH biosynthetic pathway represent a first line of Salmonella resistance against reactive oxygen and nitrogen species engendered in the context of a functional NRAMP1(R)  divalent metal transporter.
authors.affiliation: Department of Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Miryoung
authors.initials: M
authors.lastname: Song
authors.forename: Maroof
authors.initials: M
authors.lastname: Husain
authors.forename: Jessica
authors.initials: J
authors.lastname: Jones-Carson
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Calvin A
authors.initials: CA
authors.lastname: Henard
authors.forename: Andrés
authors.initials: A
authors.lastname: Vázquez-Torres
mesh_terms: D005978:Glutathione / Q000378:metabolism*; D008970:Molecular Weight; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015538:Nitrosation; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D026361:Reactive Nitrogen Species / Q000037:antagonists & inhibitors; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D012475:Salmonella / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D016877:Oxidants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D005978:Glutathione