Small-molecule inhibitor: Ac-Pro-Arg-Leu-AsnVS

Name

History: Ac-PRLNvs was one of a comprehensive series of vinyl sulfones evaluated as proteasome inhibitors by Nazif & Bogyo (2001).
Peptidases inhibited: Ac-PRLNvs is an inhibitor of the proteasome selective for catalytic subunit 2, which has trypsin-like activity (Groll & Huber, 2004).
Mechanism: Inhibition is irreversible, resulting from covalent modification of the catalytic threonine. The structure of an enzyme-inhibitor complex has been described by Groll et al. (2002).

Inhibitor class: This compound belongs to the class of Michael acceptor inhibitors. These are irreversible inhibitors specific for cysteine and threonine peptidases. The class includes vinyl sulfones and alpha, beta-unsaturated derivatives of amino acids and peptides. These inhibitors act by forming covalent bonds to the active site thiol of a cysteine peptidase. They have negligible reactivity with small-molecule thiol compounds and serine peptidases. The reaction proceeds via a Michael addition, with an attack on the beta-carbon of the inhibitor by the active site cysteine residue, followed by protonation of the alpha-carbon to form the thioether derivative. Reviewed by Powers et al. (2002), pp. 4683 - 4694.
Reviews: Powers et al. (2002)