Pérez-Mato I, Castro C, Ruiz F A, Corrales F J, Mato J M
Division of Hepatology and Gene Therapy, Department of Medicine, University of Navarra, 31008 Pamplona, Spain.
J Biol Chem. 1999 Jun 11;274(24):17075-9. doi: 10.1074/jbc.274.24.17075.
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.
S-腺苷甲硫氨酸作为许多生物甲基化反应的甲基供体，并为多胺的合成提供丙胺基团。S-腺苷甲硫氨酸由蛋氨酸和ATP通过蛋氨酸腺苷转移酶合成。调节S-腺苷甲硫氨酸合成的细胞因子尚未明确界定。在此我们表明，在大鼠肝细胞中，S-亚硝基谷胱甘肽单乙酯（一种可透过细胞的一氧化氮供体）通过S-亚硝基化使蛋氨酸腺苷转移酶失活，从而显著降低细胞内S-腺苷甲硫氨酸含量。从孵育培养基中去除一氧化氮供体可导致蛋氨酸腺苷转移酶的去亚硝基化和重新激活，并使细胞内S-腺苷甲硫氨酸水平迅速恢复。一氧化氮通过半胱氨酸121的S-亚硝基化使蛋氨酸腺苷转移酶失活。用丝氨酸取代位于半胱氨酸121附近的酸性（天冬氨酸355）或碱性（精氨酸357和精氨酸363）氨基酸，可导致一氧化氮进行S-亚硝基化并使肝脏蛋氨酸腺苷转移酶失活的能力显著降低。这些结果表明，蛋白质S-亚硝基化受靶标半胱氨酸周围的碱性和酸性氨基酸调节。
