Peptidyl cyclopropenones: Reversible inhibitors, irreversible inhibitors, or substrates of cysteine proteases?

Meital Cohen, Uriel Bretler, Amnon Albeck

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Peptidyl cyclopropenones were previously introduced as selective cysteine protease reversible inhibitors. In the present study we synthesized one such peptidyl cyclopropenone and investigated its interaction with papain, a prototype cysteine protease. A set of kinetics, biochemical, HPLC, MS, and 13C-NMR experiments revealed that the peptidyl cyclopropenone was an irreversible inhibitor of the enzyme, alkylating the catalytic cysteine. In parallel, this cyclopropenone also behaved as an alternative substrate of the enzyme, providing a product that was tentatively suggested to be either a spiroepoxy cyclopropanone or a gamma-lactone. Thus, a single family of compounds exhibits an unusual variety of activities, being reversible inhibitors, irreversible inhibitors and alternative substrates towards enzymes of the same family.

Original languageEnglish
Pages (from-to)788-799
Number of pages12
JournalProtein Science
Volume22
Issue number6
DOIs
StatePublished - Jun 2013

Bibliographical note

© 2013 The Protein Society.

Keywords

  • Alternative substrate
  • Cyclopropenone
  • Cysteine proteases
  • Enzyme inhibition
  • Irreversible inhibition

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