Naslov
Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Autori
Cvitešić, Ana ; Sabljić, Igor ; Makarević, Janja ; Abramić, Marija

Izvornik
Journal of enzyme inhibition and medicinal chemistry (1475-6366) 31 (2016), S2; 40-45

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Bacteroides thetaiotaomicron ; binding specificity ; competitive inhibitor ; family M49 ; metallopeptidase

Sažetak
Human dipeptidyl peptidase III (hDPP III), a zinc-metallopeptidase of the family M49, is an activator of the Keap1-Nrf2 cytoprotective pathway involved in defense against oxidative stress. Pathophysiological roles of DPP III have not been elucidated yet, partly due to the lack of specific inhibitors. We showed that substrate analog H-Tyr-Phe-NHOH is a strong competitive inhibitor of hDPP III, while H-Tyr-Gly-NHOH expresses much weaker inhibition. To investigate the effects of amino acid substitutions in inhibitor P1 position, we synthesized three new dipeptidyl hydroxamates and examined their influence on the activity of hDPP III and DPP III from the human gut symbiont Bacteroides thetaiotaomicron. The extent of inhibition of hDPP III, but not of bacterial enzyme, was dependent on the amino acid in P1. H-Phe-Phe-NHOH is recognized as one of the strongest inhibitors of hDPP III (Ki = 0.028 μM), and H-Phe-Leu-NHOH discriminated between human and bacterial ortholog of the M49 family.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija

POVEZANOST RADA