Inactivation of human myeloperoxidase by hydrogen peroxide

Paumann-Page, Martina; Furtmüller, Paul G.; Hofbauer, Stefan; Paton, Louise N.; Obinger, Christian; Kettle, Anthony J.

doi:10.1016/j.abb.2013.09.004

Cited by 59 publications

(56 citation statements)

References 40 publications

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“…It has been well documented that H 2 O 2 concentrations have a profound impact on the catalytic activity of MPO [3], but there is still uncertainty regarding the cause of this phenomena. During the preparation of this manuscript, Kettle et al reported that H 2 O 2 at high concentrations resulted in suicide inhibition of MPO by degradation of the heme linkage due to modification of methionine residues [33]. Interestingly, in that study HC Met 243 was not one of the methionine groups oxidized by H 2 O 2 .…”

Section: Resultsmentioning

confidence: 94%

“…It has been reported that the heme group linked to the MPO active site can be degraded by H 2 O 2 when it was added to MPO at a 1000:1 ratio and incubated for 2 hrs [33]. As is shown in Fig.…”

Section: Resultsmentioning

confidence: 97%

“…As is shown in Fig. 6A, the light chain of MPO is cleaved from MPO as we increase the concentration of BAH because the heavy chain (58.5 kDa) and light chain (14.5kDa) are linked via their covalent bound with the heme prosthetic group [33]. MPO is a dimer of heterodimers (146 kDa) consists of two identical glycosylated heavy and two light chains with the heavy chains linked by a single disulfide bond.…”

Section: Resultsmentioning

confidence: 99%

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Ordered cleavage of myeloperoxidase ester bonds releases active site heme leading to inactivation of myeloperoxidase by benzoic acid hydrazide analogs

Huang

Smith

Panizzi

2014

Archives of Biochemistry and Biophysics

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Myeloperoxidase (MPO) catalyzes the breakdown of hydrogen peroxide and the formation of the potent oxidant hypochlorous acid. We present the application of the fluorogenic peroxidase substrate 10-acetyl-3,7-dihydroxyphenoxazine (ADHP) in steady-state and transient kinetic studies of MPO function. Using initial kinetic parameters for the MPO system, we characterized under the same conditions a number of gold standards for MPO inhibition, namely 4-amino benzoic acid hydrazide (4-ABAH), isoniazid and NaN3 before expanding our focus to isomers of 4-ABAH and benzoic acid hydrazide analogs. We determined that in the presence of hydrogen peroxide that 4-ABAH and its isomer 2-ABAH are both slow-tight binding inhibitors of MPO requiring at least two steps, whereas NaN3 and isoniazid-based inhibition has a single observable step. We also determined that MPO inhibition by benzoic acid hydrazide and 4-(trifluoromethyl) benzoic acid hydrazide was due to hydrolysis of the ester bond between MPO heavy chain Glu 242 residue and the heme pyrrole A ring, freeing the light chain and heme b fragment from the larger remaining MPO heavy chain. This new mechanism would essentially indicate that the benzoic acid hydrazide analogs impart inhibition through initial ejection of the heme catalytic moiety without prior loss of the active site iron.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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Ordered cleavage of myeloperoxidase ester bonds releases active site heme leading to inactivation of myeloperoxidase by benzoic acid hydrazide analogs

Huang

Smith

Panizzi

2014

Archives of Biochemistry and Biophysics

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“…Neutrophils are the predominant WBC in the circulation and when stimulated discharge the abundant heme enzyme MPO [6]. MPO is an enzyme linked to both inflammation and oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…When stimulated, neutrophils consume oxygen in a respiratory burst that produces superoxide and hydrogen peroxide, and discharge the abundant heme enzyme myeloperoxidase (MPO) that uses hydrogen peroxide to oxidize chloride, bromide and thiocyanate to the respective hypohalous acids and hypothiocyanite. These oxidants kill ingested bacteria, but are also implicated in tissue damage associated with numerous inflammatory diseases [6]. …”

Section: Introductionmentioning

confidence: 99%

Contribution of Neutrophil Activation in the Differentiation of Urine Infection and Contamination in Pregnant Women

Şahin

Dilek²,

Güven³

et al. 2015

Gynecol Obstet Invest

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Background: Urinary tract infections are among the most common bacterial infections of humans. Urine culture is the gold standard for asymptomatic bacteriuria and pyuria is not always present in bacteriuria, nor is it specific for bacteriuria. Objective: The aim of the present study was to determine neutrophil activation and the contributions of this activation in the differentiation of infection and contamination. Methods: The serum and urine myeloperoxidase (MPO) levels of 50 pregnant females with symptoms suggesting UTI and 25 healthy non-pregnant control subjects were measured using the enzyme-linked immunosorbent assay (ELISA) method and the obtained values were compared with the results of urine microscopy and urine culture. Results: The leukocyte count in urine was significantly higher in group 1 (infection) and group 2 (contamination) when compared with the control group (group 1 mean: 18.2; group 2 mean: 14.2; control mean: 4.8; ANOVA test, p ≤ 0.00). According to the obtained ELISA values, a statistical difference in the levels of urine MPO between the patient and control groups was seen (p ≤ 0.00). There was no statistical difference among the groups for serum MPO levels (p ≥ 0.451). Conclusion: The study findings suggest that standardized measurement techniques such as dipstick screening assay for urine MPO level may be useful in differentiating infection and contamination, especially in pregnant patients.

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Myeloperoxidase Stimulates Neutrophil Degranulation

et al. 2016

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Myeloperoxidase, heme enzyme of azurophilic granules in neutrophils, is released into the extracellular space in the inflammation foci. In neutrophils, it stimulates a dose-dependent release of lactoferrin (a protein of specific granules), lysozyme (a protein of specific and azurophilic granules), and elastase (a protein of azurophilic granules). 4-Aminobenzoic acid hydrazide, a potent inhibitor of peroxidase activity of myeloperoxidase, produced no effect on neutrophil degranulation. Using signal transduction inhibitors (genistein, methoxyverapamil, wortmannin, and NiCl2), we demonstrated that myeloperoxidase-induced degranulation of neutrophils resulted from enzyme interaction with the plasma membrane and depends on activation of tyrosine kinases, phosphatidylinositol 3-kinases (PI3K), and calcium signaling. Myeloperoxidase modified by oxidative/halogenation stress (chlorinated and monomeric forms of the enzyme) lost the potency to activate neutrophil degranulation.

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Inactivation of human myeloperoxidase by hydrogen peroxide

Abstract: Graphical abstract

Cited by 59 publications

References 40 publications

Ordered cleavage of myeloperoxidase ester bonds releases active site heme leading to inactivation of myeloperoxidase by benzoic acid hydrazide analogs

Ordered cleavage of myeloperoxidase ester bonds releases active site heme leading to inactivation of myeloperoxidase by benzoic acid hydrazide analogs

Contribution of Neutrophil Activation in the Differentiation of Urine Infection and Contamination in Pregnant Women

Myeloperoxidase Stimulates Neutrophil Degranulation

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