Methionine Adenosyltransferase S-Nitrosylation Is Regulated by the Basic and Acidic Amino Acids Surrounding the Target Thiol

S -Adenosylmethionine serves as the methyl donor for many biological methylation reactions and provides the propylamine group for the synthesis of polyamines. S -Adenosylmethionine is synthesized from methionine and ATP by the enzyme methionine adenosyltransferase. The cellular factors regulating S -adenosylmethionine synthesis have not been well defined. Here we show that in rat hepatocytes S -nitrosoglutathione monoethyl ester, a cell-permeable nitric oxide donor, markedly reduces cellular S -adenosylmethionine content via inactivation of methionine adenosyltransferase by S -nitrosylation. Removal of the nitric oxide donor from the incubation medium leads to the denitrosylation and reactivation of methionine adenosyltransferase and to the rapid recovery of cellular S -adenosylmethionine levels. Nitric oxide inactivates methionine adenosyltransferase via S -nitrosylation of cysteine 121. Replacement of the acidic (aspartate 355) or basic (arginine 357 and arginine 363) amino acids located in the vicinity of cysteine 121 by serine leads to a marked reduction in the ability of nitric oxide to S -nitrosylate and inactivate hepatic methionine adenosyltransferase. These results indicate that protein S -nitrosylation is regulated by the basic and acidic amino acids surrounding the target cysteine.