title: Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III.
abstract: 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.
authors.affiliation: a Division of Organic Chemistry and Biochemistry , and.
authors.forename: Ana
authors.initials: A
authors.lastname: Cvitešić
authors.affiliation: b Division of Physical Chemistry , Ruđer Bošković Institute , Bijenička cesta 54 , Zagreb , Croatia.
authors.forename: Igor
authors.initials: I
authors.lastname: Sabljić
authors.affiliation: a Division of Organic Chemistry and Biochemistry , and.
authors.forename: Janja
authors.initials: J
authors.lastname: Makarević
authors.affiliation: a Division of Organic Chemistry and Biochemistry , and.
authors.forename: Marija
authors.initials: M
authors.lastname: Abramić
mesh_terms: D000070077:Bacteroides thetaiotaomicron / Q000201:enzymology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III
keywords: Bacteroides thetaiotaomicron; binding specificity; competitive inhibitor; family M49; metallopeptidase