Inactivation and dissociation of S-adenosylmethionine synthetase by modification of sulfhydryl groups and its possible occurrence in cirrhosis.
Catalytically active human and rat liver S-adenosylmethionine synthetase exists mainly in tetramer and dimer form. In liver biopsy samples from cirrhotic patients a marked reduction in total S-adenosylmethionine synthetase activity and a specific loss of the tetrameric form of the enzyme exist. We have investigated the possible role of sulfhydryl groups in maintaining the structure and activity of S-adenosylmethionine synthetase. Both forms of S-adenosylmethionine synthetase are rapidly inactivated by N-ethylmaleimide, and the loss of enzyme activity correlates with the incorporation of approximately 2 moles N-ethylmaleimide per mole of subunit. In addition, reaction with N-ethylmaleimide resulted in displacement of the tetramer-dimer equilibrium of the enzyme toward the dimer, but no monomer was detected under these conditions. A catalytically active monomeric S-adenosylmethionine synthetase was detected in the cytosolic extract from a liver biopsy sample from a cirrhotic patient, supporting our model for the structure of S-adenosylmethionine synthetase. Because treatment of S-adenosylmethionine synthetase with N-ethylmaleimide resembles the situation of this enzyme in cirrhotic patients, it is proposed that impaired protection of the enzyme from oxidizing agents caused by a decreased synthesis of glutathione can explain the diminished synthesis of S-adenosylmethionine in liver cirrhosis.
Corrales
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Metabolismo, Nutrición y Hormonas, Fundación Jiménez Díaz, Instituto de Biomedicino del C.S.I.C., Madrid, Spain.
Cabrero
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C
Pajares
M A
MA
Ortiz
P
P
Martin-Duce
A
A
Mato
J M
JM
D000818:Animals; D002850:Chromatography, Gel; D005033:Ethylmaleimide / Q000494:pharmacology; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology*; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008970:Molecular Weight; D010084:Oxidation-Reduction; D051381:Rats; D013438:Sulfhydryl Compounds; D014166:Transferases / Q000378:metabolism*
D013438:Sulfhydryl Compounds; D014166:Transferases; D008716:Methionine Adenosyltransferase; D005978:Glutathione; D005033:Ethylmaleimide