title: N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor.
abstract: Myeloperoxidase (MPO) plays important roles in disease by increasing oxidative and nitrosative stress and oxidizing lipoproteins. Here we report N-acetyl lysyltyrosylcysteine amide (KYC) is an effective inhibitor of MPO activity. We show KYC inhibits MPO-mediated hypochlorous acid (HOCl) formation and nitration/oxidation of LDL. Disulfide is the major product of MPO-mediated KYC oxidation. KYC (≤4,000 μM) does not induce cytotoxicity in bovine aortic endothelial cells (BAECs). KYC inhibits HOCl generation by phorbol myristate acetate (PMA)-stimulated neutrophils and human promyelocytic leukemia (HL-60) cells but not superoxide generation by PMA-stimulated HL-60 cells. KYC inhibits MPO-mediated HOCl formation in BAEC culture and protects BAECs from MPO-induced injury. KYC inhibits MPO-mediated lipid peroxidation of LDL whereas tyrosine (Tyr) and tryptophan (Trp) enhance oxidation. KYC is unique as its isomers do not inhibit MPO activity, or are much less effective. Ultraviolet-visible spectral studies indicate KYC binds to the active site of MPO and reacts with compounds I and II. Docking studies show the Tyr of KYC rests just above the heme of MPO. Interestingly, KYC increases MPO-dependent H₂O₂ consumption. These data indicate KYC is a novel and specific inhibitor of MPO activity that is nontoxic to endothelial cell cultures. Accordingly, KYC may be useful for treating MPO-mediated vascular disease.
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Xigang
authors.initials: X
authors.lastname: Jing
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Jianhai
authors.initials: J
authors.lastname: Du
authors.forename: Tongju
authors.initials: T
authors.lastname: Guan
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.forename: Deron W
authors.initials: DW
authors.lastname: Jones
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Gourlay
authors.forename: Keith T
authors.initials: KT
authors.lastname: Oldham
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hillery
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D055162:Biocatalysis; D002417:Cattle; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D018922:HL-60 Cells; D054879:Halogenation / Q000187:drug effects; D006801:Humans; D006997:Hypochlorous Acid / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009504:Neutrophils / Q000201:enzymology; D009566:Nitrates / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C588227:N-acetyllysyltyrosylcysteine amide; D009566:Nitrates; D009842:Oligopeptides; D006997:Hypochlorous Acid; D009195:Peroxidase
keywords: apolipoprotein A1; chlorination; hypochlorous acid; lipid peroxidation; low density lipoproteins; nitration; nitrogen dioxide