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Myeloperoxidase-catalyzed chlorination: the quest for the active species
Authors:Ramos Daniel R  García M Victoria  Canle L Moisés  Santaballa J Arturo  Furtmüller Paul G  Obinger Christian
Institution:

aChemical Reactivity and Photoreactivity Group, Department of Physical Chemistry and Chemical Engineering I, University of A Coruña, Alejandro de la Sota 1, E-15008 A Coruña, Spain

bDepartment of Chemistry, Division of Biochemistry, BOKU-University of Natural Resources and Applied Life Sciences, Muthgasse 18, A-1190 Vienna, Austria

Abstract:Myeloperoxidase (MPO) is a dominating enzyme of circulating polymorphonuclear neutrophils that catalyzes the two-electron oxidation of chloride, thereby producing the strong halogenating agent hypochlorous acid (ClO?/HOCl). In absence of MPO the tripeptide Pro-Gly-Gly reacts with HOCl faster than the amino acid taurine (2-aminoethanesulfonic acid, Tau), while the MPO-mediated chlorination shows reverse order. A comparative study of the enzymatic oxidation of both substrates at pH 4.0–6.0, varying H2O2 concentration is presented. Initial and equilibrium rates studies have been carried on, reaction rates in the latter being slower due to the chemical equilibrium between MPO-I and MPO-II–HO2. A maximum of chlorination rate is observed for Pro-Gly-Gly and Tau when H2O2] ≈ 0.3–0.7 mM and pH ≈ 4.5–5.0. Several mechanistic possibilities are considered, the proposed one implies that chlorination takes place via two pathways. One, for bulkier substrates, involves chlorination by free HOCl outside the heme cavity; ClO? is released from the active center, diffuses away the heme cavity, and undergoes protonation to HOCl. The other implies the existence of compound I–Cl? complex (MPO-I–Cl), capable of chlorinating smaller substrates in the heme pocket. Electronic structure calculations show the size of Pro-Gly-Gly comparable to the available gap in the substrate channel, this tripeptide being unable to reach the active site, and its chlorination is only possible by free HOCl outside the enzyme.
Keywords:Myeloperoxidase  Chlorination  Hypochlorous acid  Hypochlorite  Chloramines  Tripeptide  Pro-Gly-Gly
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