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Cited by 150Neutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stressBioactive Compounds and Antitumor Agents

The DOI matches its Crossref record; 197 of the 197 references it cites were found in a registry or an index.

The many roles of myeloperoxidase: From inflammation and immunity to biomarkers, drug metabolism and drug discovery

Open access
Siraki, Arno G.·2021·Redox Biology
DOI 10.1016/j.redox.2021.102109PMC PMC8403760
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Abstract

This review provides a practical guide to myeloperoxidase (MPO) and presents to the reader the diversity of its presence in biology. The review provides a historical background, from peroxidase activity to the discovery of MPO, to its role in disease and drug development. MPO is discussed in terms of its necessity, as specific individuals lack MPO expression. An underlying theme presented throughout brings up the question of the benefit and burden of MPO activity. Enzyme structure is discussed, including accurate masses and glycosylation sites. The catalytic cycle of MPO and its corresponding pathways are presented, with a discussion of the importance of the redox couples of the different states of MPO. Cell lines expressing MPO are discussed and practically summarized for the reader, and locations of MPO (primary and secondary) are provided. Useful methods of MPO detection are discussed, and how these can be used for studying disease processes are implied through the presentation of MPO as a biomarker. The presence of MPO in neutrophil extracellular traps is presented, and the activators of the former are provided. Lastly, the transition from drug metabolism to a target for drug development is where the review concludes.

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Graphical abstract
Graphical abstract CC BY-NC-ND · PubMed Central
Fig. 1 A timeline of MPO from discovery, function, inhibition, and disease. References indicated have been added for the seminal or foundational publication or first reports. References used to create the timeline: Peroxidase staining [4,5,18], Discovery [19] bactericidal activity [9]; MPO as % dry protein [20]; cells and cellular location [21]; Halogenation as bactericidal mechanism [11,22]; Anti-neutrophil cytoplasmic antibodies are anti-MPO [[23], [24], [25]]; MPO in atherosclerosis [26,27]; cardiotoxicity [[28], [29], [30], [31]]; neurotoxicity [32,33]; drug metabolism [[34], [35], [36]]; requirement for neutrophil extracellular trap formation [37,38]; MPO clinical inhibitor leads [[39], [40], [41]]; MPO levels in COVID-19 and thrombosis events [[42], [43], [44]].
Fig. 1 A timeline of MPO from discovery, function, inhibition, and disease. References indicated have been added for the seminal or foundational publication or first reports. References used to create the timeline: Peroxidase staining [4,5,18], Discovery [19] bactericidal activity [9]; MPO as % dry protein [20]; cells and cellular location [21]; Halogenation as bactericidal mechanism [11,22]; Anti-neutrophil cytoplasmic antibodies are anti-MPO [[23], [24], [25]]; MPO in atherosclerosis [26,27]; cardiotoxicity [[28], [29], [30], [31]]; neurotoxicity [32,33]; drug metabolism [[34], [35], [36]]; requirement for neutrophil extracellular trap formation [37,38]; MPO clinical inhibitor leads [[39], [40], [41]]; MPO levels in COVID-19 and thrombosis events [[42], [43], [44]].CC BY-NC-ND · PubMed Central
Fig. 2 Neutrophils from MPO-normal and MPO-deficient donors demonstrate the haem colour itself as a clear indicator for the presence of MPO (modified from [1], with permission). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2 Neutrophils from MPO-normal and MPO-deficient donors demonstrate the haem colour itself as a clear indicator for the presence of MPO (modified from [1], with permission). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)CC BY-NC-ND · PubMed Central
Fig. 3 The MPO active site. The haem prosthetic group is covalently bound to the protein via three amino acid linkages (from [2], with permission).
Fig. 3 The MPO active site. The haem prosthetic group is covalently bound to the protein via three amino acid linkages (from [2], with permission).CC BY-NC-ND · PubMed Central
Fig. 4 Different states of MPO and their associated redox potentials. The cycle begins with the “Resting” state, where the redox status of the iron centre of the protoporphyrin IX (haem) active site is indicated. MPO becomes activated in the presence of H2O2, which led to Compound I, which contains the ferryl haem species ([FeIVO]●+) and contains a delocalized free radical. Compound I will transform by either halogen oxidation (“pseudo halogen” is indicated to include SCN−, Cl−, Br−, I−) back to the Resting state, or the peroxidase cycle where xenobiotics and endobiotics (“Substrate”) can be oxidized, resulting in Compound II. In the presence of H2O2 and the absence of substrate, Compound III may form. Compound III can also form by certain substrates, or via reduction of the Resting enzyme to produce Ferrous MPO. ∗ Redox potentials from [95]. These values are useful in predicting if a particular substrate can reduce Compound I/II efficiently. As is apparent, Compound I is capable of oxidizing more substrates than Compound II. ** Indicates the direct conversion of ferrous myeloperoxidase to compound II by hydrogen peroxide [95].
Fig. 4 Different states of MPO and their associated redox potentials. The cycle begins with the “Resting” state, where the redox status of the iron centre of the protoporphyrin IX (haem) active site is indicated. MPO becomes activated in the presence of H2O2, which led to Compound I, which contains the ferryl haem species ([FeIVO]●+) and contains a delocalized free radical. Compound I will transform by either halogen oxidation (“pseudo halogen” is indicated to include SCN−, Cl−, Br−, I−) back to the Resting state, or the peroxidase cycle where xenobiotics and endobiotics (“Substrate”) can be oxidized, resulting in Compound II. In the presence of H2O2 and the absence of substrate, Compound III may form. Compound III can also form by certain substrates, or via reduction of the Resting enzyme to produce Ferrous MPO. ∗ Redox potentials from [95]. These values are useful in predicting if a particular substrate can reduce Compound I/II efficiently. As is apparent, Compound I is capable of oxidizing more substrates than Compound II. ** Indicates the direct conversion of ferrous myeloperoxidase to compound II by hydrogen peroxide [95].CC BY-NC-ND · PubMed Central
Fig. 5 The presence of MPO in tissues, and association with various disease states. Please refer to the text description of locations for greater detail. MPO usefulness as a biomarker in disease states.
Fig. 5 The presence of MPO in tissues, and association with various disease states. Please refer to the text description of locations for greater detail. MPO usefulness as a biomarker in disease states.CC BY-NC-ND · PubMed Central
Fig. 6 Fluorescent and magnetic resonance detection methodology. MPO peroxidase activity catalyzes the one-electron oxidation of the substrate, which converts it to a free radical metabolite. Although the free radical metabolite was proposed to bind to protein [126], there is more evidence to suggest that a quinoneimine or o-quinone serotonin metabolite is the proximate electrophile that will bind to protein [127,128]. (Modified from [126]).
Fig. 6 Fluorescent and magnetic resonance detection methodology. MPO peroxidase activity catalyzes the one-electron oxidation of the substrate, which converts it to a free radical metabolite. Although the free radical metabolite was proposed to bind to protein [126], there is more evidence to suggest that a quinoneimine or o-quinone serotonin metabolite is the proximate electrophile that will bind to protein [127,128]. (Modified from [126]).CC BY-NC-ND · PubMed Central
Fig. 7 Major NET formation steps and summary of inducers of NETosis. For illustrative purposes, the small green spheres in the NET represent MPO, which were housed in the primary granules (large green spheres). ANCA-induced activation is suggested to require neutrophil priming in advance. TIM-3 is a surface protein on T-cells that is proposed to activate NETosis. DAMPs (damage associated molecular patterns) have been described in the text, but include mitochondrial DNA, galectin-3, for example. Uric acid microcrystals, and other microcrystals can activate NETosis, and so could the combination of the cytokines IL-6 and TNFα. Concepts and findings were applied in this figure from [42,164,169]. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 7 Major NET formation steps and summary of inducers of NETosis. For illustrative purposes, the small green spheres in the NET represent MPO, which were housed in the primary granules (large green spheres). ANCA-induced activation is suggested to require neutrophil priming in advance. TIM-3 is a surface protein on T-cells that is proposed to activate NETosis. DAMPs (damage associated molecular patterns) have been described in the text, but include mitochondrial DNA, galectin-3, for example. Uric acid microcrystals, and other microcrystals can activate NETosis, and so could the combination of the cytokines IL-6 and TNFα. Concepts and findings were applied in this figure from [42,164,169]. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)CC BY-NC-ND · PubMed Central
Fig. 8 Chemical structure of AZD4831 (AstraZeneca), currently in phase II clinical trials, and PF06282999 (Pfizer) did not proceed from Phase I clinical trials [3].
Fig. 8 Chemical structure of AZD4831 (AstraZeneca), currently in phase II clinical trials, and PF06282999 (Pfizer) did not proceed from Phase I clinical trials [3].CC BY-NC-ND · PubMed Central

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Cites

Research works printed but not linked: 6

  1. Agner, 1941, Verdoperoxidase: a ferment isolated from leukocytes, Acta Physiol. Scand., 2, 1
  2. Mason, 1987, Free-radical metabolite formation by mammalian peroxidases, Life Sci. Res. Rep., 37, 67
  3. Lanza, 1998, Clinical manifestation of myeloperoxidase deficiency, J. Mol. Med., 76, 676, 10.1007/s001090050267 · DOI
  4. Qasim A, P.J. ANCA Positive Vasculitis. StatPearls [Internet] 2020 2021 Jan 5; Available from: https://www.ncbi.nlm.nih.gov/books/NBK554372/.
  5. Delgado-Rizo, 2017, Neutrophil extracellular traps and its implications in inflammation: an overview, Front. Immunol., 8
  6. Subrahmanyam, 1991, Hydroxylation of phenol to hydroquinone catalyzed by a human myeloperoxidase-superoxide complex: possible implications in benzene-induced myelotoxicity, Free Radic. Res. Commun., 15, 285, 10.3109/10715769109105224 · DOI

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Metadata

Authors
Siraki, A. G.
Affiliations
University of Alberta (CA)
Corresponding author
Siraki, Arno G.
ORCID
Siraki, Arno G.
Venue
Redox Biology
Publisher
Elsevier BV
Published
2021-10
Volume
46
Pages
102109
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2021.102109
PMC
PMC8403760
OpenAlex
W3195599952
Cited by
150
References
197
Citations by year
2026: 32 · 2025: 36 · 2024: 36 · 2023: 28 · 2022: 17 · 2021: 1
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-04878, RGPIN-2020-06305)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords
myeloperoxidase, inflammation, immunity, biomarkers, drug metabolism, drug discovery, redox couples, neutrophil extracellular traps
MeSH terms
Pharmaceutical Preparations, Humans, Inflammation, Peroxidase, Neutrophils, Biomarkers, Drug Discovery

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