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N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor. J Lipid Res 2013 Nov;54(11):3016-29

Date

07/26/2013

Pubmed ID

23883583

Pubmed Central ID

PMC3793606

DOI

10.1194/jlr.M038273

Scopus ID

2-s2.0-84885993885   15 Citations

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.

Author List

Zhang H, Jing X, Shi Y, Xu H, Du J, Guan T, Weihrauch D, Jones DW, Wang W, Gourlay D, Oldham KT, Hillery CA, Pritchard KA Jr

Authors

David M. Gourlay MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Keith T. Oldham MD Professor in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Dorothee Weihrauch DVM, PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Aorta
Biocatalysis
Cattle
Endothelial Cells
HL-60 Cells
Halogenation
Humans
Hypochlorous Acid
Lipid Peroxidation
Neutrophils
Nitrates
Oligopeptides
Oxidation-Reduction
Peroxidase
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