Inactivation and dissociation of s ‐adenosylmethionine synthetase by modification of sulfhydryl groups and its possile 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.