Biochemistry (Washington) 1985-07-16

5-Oxoprolinal: transition-state aldehyde inhibitor of pyroglutamyl-peptide hydrolase.

T C Friedman, T B Kline, S Wilk

Index: Biochemistry 24 , 3907, (1985)

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Abstract

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.