Inhibitors of Bacterial Cystathionine β-Lyase:  Leads for New Antimicrobial Agents and Probes of Enzyme Structure and Function Journal Articles uri icon

  • Overview
  • Research
  • Identity
  • Additional Document Info
  • View All


  • The biosynthesis of methionine is an attractive antibiotic target given its importance in protein and DNA metabolism and its absence in mammals. We have performed a high-throughput screen of the methionine biosynthesis enzyme cystathionine beta-lyase (CBL) against a library of 50 000 small molecules and have identified several compounds that inhibit CBL enzyme activity in vitro. These hit molecules were of two classes: those that blocked CBL activity with mixed steady-state inhibition and those that covalently interacted with the enzyme at the active site pyridoxal phosphate cofactor with slow-binding inhibition kinetics. We determined the crystal structure of one of the slow-binding inhibitors in complex with CBL and used this structure as a guide in the synthesis of a small, focused library of analogues, some of which had improved enzyme inhibition properties. These studies provide the first lead molecules for antimicrobial agents that target cystathionine beta-lyase in methionine biosynthesis.


  • Ejim, Linda J
  • Blanchard, Jan E
  • Koteva, Kalinka P
  • Sumerfield, Rachael
  • Elowe, Nadine H
  • Chechetto, Jonathan D
  • Brown, Eric
  • Junop, Murray S
  • Wright, Gerard

publication date

  • February 1, 2007

has subject area