5-Oxoprolinal: Transition-State Aldehyde Inhibitor of Pyroglutamyl-Peptide Hydrolase

Pyroglutamyl-peptide hydrolase (EC 3.4.11.8) removes the N-terminal pyroglutamyl residue from pyroglutamyl-containing peptides such as thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing hormone (LH-RH), neurotensin, and bombesin. The aldehyde analogue of pyroglutamate, 5-oxoprolinal, was synthesized as an active site directed transition-state inhibitor of the enzyme. 5-Oxoprolinal was found to be a potent (Ki = 26 nM) and specific competitive inhibitor of pyroglutamyl-peptide hydrolase. Other aldehydes tested inhibited the enzyme only weakly or not at all. 5-Oxoprolinal blocked the degradation of LH-RH by purified pyroglutamyl-peptide hydrolase. The inhibitor, when injected into mice, inhibited the enzyme after 10 and 30 min. 5-Oxoprolinal should be of value in studies probing the biological significance of pyroglutamyl-peptide hydrolase.