Myeloperoxidase-catalyzed chlorination: The quest for the active species

Ramos, Daniel R.; García, M. V.; Canle, Moisés; Santaballa, J. Arturo; Furtmüller, Paul G.; Obinger, Christian

doi:10.1016/j.jinorgbio.2008.01.003

Cited by 29 publications

(20 citation statements)

References 36 publications

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“…In view of their bulk, steric considerations make it unlikely that these targets can have efficient access to the MPO active site, thus suggesting that free HOCl must be the oxidizing agent in these cases. Indeed, a recent study (Ramos et al 2008) suggests that even targets as small as a tri-peptide are unable to access the active site. A synthesis of the available data might suggest that small molecules, particularly the amino acid taurine which is present at mM concentrations within the neutrophil cytoplasm, access the enzyme active site and in effect act to limit reactivity with other targets (including MPO itself, see below) within the cell (Marcinkiewicz et al 1995).…”

Section: Hypochlorous Acidmentioning

confidence: 99%

Neutrophil Myeloperoxidase: Soldier and Statesman

Prokopowicz¹,

Marcinkiewicz

Katz³

et al. 2011

Arch. Immunol. Ther. Exp.

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Myeloperoxidase (MPO) is a major protein constituent of the primary granules of vertebrate neutrophils. It catalyses the hydrogen peroxide-mediated oxidation of halide ions to hypohalous acids, especially HOCl. These reactive oxygen species can participate in a variety of secondary reactions, leading to modifications of amino acids and many types of biological macromolecules. The classic paradigm views MPO as a component of the phagocyte oxygen-dependent intracellular microbicidal system, and thus an important arm of the effector phase of innate immune responses. However, the limited immunodeficiency associated with lack of MPO in mouse and human models has challenged this paradigm. In this review we examine more recent information on the interaction between MPO, its bioreactive reaction products, and targets within the inflammatory microenvironment. We propose that two assumptions of the current model may require revisiting. First, many important targets of MPO modification are extracellular, rather than present only within the phagolysosome, such as various components of neutrophil extracellular traps. Second, we suggest that the pro-inflammatory pathological role of MPO may be a particular feature of chronic inflammation. In the physiological setting of acute neutrophil-mediated inflammation MPO may also form part of a negative feedback loop which down-regulates inflammation, limits tissue damage, and facilitates the switch from innate to adaptive immunity. This different perspective on this well-studied enzyme may usefully inform further research into its function in health and disease.

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Section: Hypochlorous Acidmentioning

confidence: 99%

Neutrophil Myeloperoxidase: Soldier and Statesman

Prokopowicz¹,

Marcinkiewicz

Katz³

et al. 2011

Arch. Immunol. Ther. Exp.

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“…There is another MPOspecific effect. On the quest for the active species involved in substrate modifications, it has been found that small substrates like taurine were directly chlorinated by the MPO-compound I-chloride complex, whereas in the presence of more bulky substrates the hypochlorite ion -OCl was primarily formed that protonates to HOCl [36]. It remains unknown if there is a direct chlorination of NH 4 + by the transient MPO-compound I-chloride complex or a reaction between -OCl and NH 4 + in the substrate binding pocket of MPO.…”

Section: Discussionmentioning

confidence: 99%

Interaction of hypochlorous acid and myeloperoxidase with phosphatidylserine in the presence of ammonium ions

Flemmig

Arnhold

2010

Journal of Inorganic Biochemistry

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“…The reactivity of MPO-I with Cl À leading to HOCl is pH dependent, being favored at acidic pH as indicated by its apparent second-order rate constants 3.9 Â 10 6 mol À1 L s À1 and 2.5 Â 10 4 mol À1 L s À1 , at pH 5.0 and 7.0, respectively [36]. In addition, the reactivity of HOCl is increased in its protonated form [45,46], the predominate species at pH 5.0 (pKa 7.44). For this reason, we hypothesized that by conducting the reaction at pH 5.0, the dependence of Br À could be diminished or totally unnecessary.…”

Section: Discrimination Between Mpo and Epomentioning

confidence: 99%

Dansylglycine, a fluorescent probe for specific determination of halogenating activity of myeloperoxidase and eosinophil peroxidase

Bertozo

Zeraik

Ximenes

2017

Analytical Biochemistry

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Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are enzymes present in neutrophil and eosinophil leukocytes, respectively. Here, we present the development of a sensitive and specific assay for determination of the halogenating enzymatic activity of MPO and EPO based on the electrophilic attack of HOCl and HOBr on aromatic ring of dansylglycine (DG). We found that the intrinsic fluorescence of DG was promptly depleted by the action of these acids. In the presence of the enzymes, the fluorescence bleaching was dependent of chloride (Cl) and bromide (Br), which makes the assay able to distinguish the halogenating from the peroxidase activity. A linear correlation was obtained between the hydrogen peroxide (HO) concentration and the fluorescent decay. Similarly, the enzyme activity was measured by keeping constant HO. The method was applied for studding MPO/EPO specific inhibitors as 5-fluortryptamine (reversible inhibitor) and 4-hydroxybenzhydrazide (irreversible inhibitor). Differently of the taurine chloramine/3,3',5,5'-tetramethylbenzidine assay, which is among the most used technique, the dansylglycine assay was able to differentiate these inhibitors based on their kinetic behavior. In conclusion, this assay can differentiate the peroxidase and halogenating activity of MPO and EPO. Moreover, the method is adequate for real-time measurement of the production of HOCl and HOBr.

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Myeloperoxidase-catalyzed chlorination: The quest for the active species

Cited by 29 publications

References 36 publications

Neutrophil Myeloperoxidase: Soldier and Statesman

Neutrophil Myeloperoxidase: Soldier and Statesman

Interaction of hypochlorous acid and myeloperoxidase with phosphatidylserine in the presence of ammonium ions

Dansylglycine, a fluorescent probe for specific determination of halogenating activity of myeloperoxidase and eosinophil peroxidase

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