In Salmonella enterica, the Gcn5-Related Acetyltransferase MddA (Formerly YncA) Acetylates Methionine Sulfoximine and Methionine Sulfone, Blocking Their Toxic Effects

Abstract

Protein and small-molecule acylation reactions are widespread in nature. Many of the enzymes catalyzing acylation reactions belong to theGcn5-relatedN-acetyltransferase (GNAT; PF00583) family, named after the yeast Gcn5 protein. The genome ofSalmonella entericaserovar Typhimurium LT2 encodes 26 GNATs, 11 of which have no known physiological role. Here, we providein vivoandin vitroevidence for the role of the MddA (methioninederivativedetoxifier; formerly YncA) GNAT in the detoxification of oxidized forms of methionine, including methionine sulfoximine (MSX) and methionine sulfone (MSO). MSX and MSO inhibited the growth of anS. entericaΔmddAstrain unless glutamine or methionine was present in the medium. We used anin vitrospectrophotometric assay and mass spectrometry to show that MddA acetylated MSX and MSO. AnmddA+strain displayed biphasic growth kinetics in the presence of MSX and glutamine. Deletion of two amino acid transporters (GlnHPQ and MetNIQ) in a ΔmddAstrain restored growth in the presence of MSX. Notably, MSO was transported by GlnHPQ but not by MetNIQ. In summary, MddA is the mechanism used byS. entericato respond to oxidized forms of methionine, which MddA detoxifies by acetyl coenzyme A-dependent acetylation.