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.
Pérez-Mato
I
I
Division of Hepatology and Gene Therapy, Department of Medicine, University of Navarra, 31008 Pamplona, Spain.
Castro
C
C
Ruiz
F A
FA
Corrales
F J
FJ
Mato
J M
JM
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009569:Nitric Oxide / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012436:S-Adenosylmethionine / Q000378:metabolism; D026422:S-Nitrosoglutathione; D013438:Sulfhydryl Compounds
D000596:Amino Acids; D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D012436:S-Adenosylmethionine; D008715:Methionine; D008716:Methionine Adenosyltransferase; D005978:Glutathione