Inactivation of human S-adenosylhomocysteine hydrolase by covalent labeling of cysteine 195 with thionucleoside derivatives

Bioorg Med Chem Lett. 2004 Dec 6;14(23):5803-7. doi: 10.1016/j.bmcl.2004.09.051.

Abstract

A new series of 5'-thioadenosine derivatives 1-4 were synthesized for selectively targeting (195)Cys of human AdoHcy hydrolase. Their incubation with the enzyme resulted in time- and concentration-dependent inactivation, without major modifications of the NAD(+)/NADH ratio. The electrospray mass analysis of the inactivated enzyme with 1, 2, 3, and 4b showed that inhibition was accompanied by the formation of a specific and covalent labeling of each AdoHcy hydrolase subunit. Proteolytic cleavage (endo-Lys-C) and subsequent peptide characterization of the labeled enzyme revealed that (195)Cys was the residue modified during the inactivation process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylhomocysteinase / antagonists & inhibitors*
  • Adenosylhomocysteinase / metabolism
  • Cysteine / chemistry*
  • Cysteine / pharmacology
  • Humans
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Thionucleosides / chemistry*
  • Thionucleosides / pharmacology

Substances

  • Protease Inhibitors
  • Thionucleosides
  • Adenosylhomocysteinase
  • Cysteine