Slow tight-binding inhibition of prolyl endopeptidase by benzyloxycarbonyl-prolyl-prolinal.

摘要: Prolyl endopeptidase is a serine proteinase that specifically cleaves peptides on the carboxy side of proline residues. Wilk & Orlowski [(1983) J. Neurochem. 41, 69-75] have shown benzyloxycarbonyl-prolyl-prolinal (Z-prolyl-prolinal) potent inhibitor prolyl endopeptidase. We show Z-prolyl-prolinal slow-binding mouse brain with Ki 0.35 +/- 0.05 nM. Kinetic analysis indicates mechanism simple, but slow, reversible equilibrium between free and bound enzyme (E + I in EI) rate constants for association (kon) dissociation (koff) 1.6 X 10(5) M-1.s-1 approx. 4 10(-5) s-1 respectively. Slow-binding inhibition dependent presence aldehyde group since alcohol (Z-prolyl-prolinol) rapid 50,000-fold poorer (Ki 19 microM). from human also inhibited by kinetics similar to those enzyme.