Inactivation and dissociation of s-adenosylmethionine synthetase by modification of sulfhydryl groups and its possile occurrence in cirrhosis

Authors

  • Fernando Corrales,

    1. Metabolismo, Nutrición y Hormonas, Fundación Jiménez Diaz and Instituto de Biomedicina del C. S. I. C., Madrid, Spain
    Search for more papers by this author
  • Carmen Cabrero,

    1. Metabolismo, Nutrición y Hormonas, Fundación Jiménez Diaz and Instituto de Biomedicina del C. S. I. C., Madrid, Spain
    Search for more papers by this author
  • Maria A. Pajares,

    1. Metabolismo, Nutrición y Hormonas, Fundación Jiménez Diaz and Instituto de Biomedicina del C. S. I. C., Madrid, Spain
    Search for more papers by this author
  • Pablo Ortiz,

    1. Metabolismo, Nutrición y Hormonas, Fundación Jiménez Diaz and Instituto de Biomedicina del C. S. I. C., Madrid, Spain
    Search for more papers by this author
  • Antonio Martin-Duce,

    1. Servicio de Cirugia de Digestivo, Hospital de Alcalá de Henares, Madrid, Spain
    Search for more papers by this author
  • Jose M. Mato

    Corresponding author
    1. Metabolismo, Nutrición y Hormonas, Fundación Jiménez Diaz and Instituto de Biomedicina del C. S. I. C., Madrid, Spain
    • Metabolismo, Nutricion y Hormonas, Fundacion Jimenez Diaz, Instituto de Biomedicina del CSIC, Reyes Catolicos, 2, 28040 Madrid, Spain
    Search for more papers by this author

Abstract

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.

Ancillary