Events associated with phagocytolytic activity of PMN cells (Homo sapiens)

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4, 253, 5, 2711, 13-158, 102013, 228, 109, 2110, 17, 191, 125, 13, 22, 24, 262, 182, 66, 164, 10, 17phagocytic vesicle lumencytosolcell wallhost cellcytosolhost cellbacterialbacterial cellPeptidyl-Lys-NH2H2Oferriheme b(1-) MPO:ferrihemeferriheme b(1-) Peptidyl-Lys-NCl2Peptidyl-Cys-SHPeptidyl-Cys-SSCNH2OPeptidyl-Lys-NHClpeptidoglycan-chloramideROS and RNSproduction inphagocytesMPO (165-278) nitryl chloride Cl-nitryl chlorideGlcNAc-(1-->4)-MurNAc-L-Ala-gamma-D-Glu-N(6)-(beta-D-Asp)-L-Lys-(D-Ala) Peptidyl-Cys-SHNO2MPO (279-745) Cell surfacepeptidoglycan-NHAcGlcNAc-(1-->4)-MurNAc-L-Ala-gamma-D-Glu-N(6)-(beta-D-Asp)-L-Lys-(D-Ala) H2O2Unsaturated lipidH2OH2OMurNAc Fe2+OSCN-HOClLipid-ClbetaGlcNAcPeptidyl-Cys-SClHOCl, NO2ClSCN(-)MurNAc:PeptideCl-LPO:ferrihemeH2OMPO (165-278) Peptide Peptidyl-Cys-SOHH2OGlcNAc(1-->4)MurNAc:L-Ala-gamma-D-Glu-L-Lys-(D-Ala)2 nitriteH2OLPO MPO:ferriheme:bacterial cell surfaceCl-H+HOCl H+HOClMPO (279-745) H2OGlcNAc(1-->4)MurNAc:L-Ala-gamma-D-Glu-L-Lys-(D-Ala)2 ferriheme b(1-) H2O2H2OCell surface 7, 2326


Description

When neutrophils engulf bacteria they enclose them in small vacuoles (phagosomes) into which superoxide is released by activated NADPH oxidase (NOX2) on the internalized neutrophil membrane. The directional nature of NOX2 activity creates a charge imbalance that must be counteracted to prevent depolarization of the membrane and the shutdown of activity (Winterbourn CC et al. 2016). Also, protons are produced in the cytosol and consumed in the external compartment (for example, the phagosome) through the dismutation of superoxide. Both situations are largely overcome by a balancing flow of protons transported by voltage-gated proton channels, primarily VSOP/HV1, which are activated in parallel with the oxidase (Demaurex N & El Chemaly A 2010; El Chemaly A et al. 2010; Petheo GL et al. 2010; Kovacs I et al. 2014; Henderson LM et al. 1987, 1988). The pH of the phagosome is regulated by these activities. In contrast to the phagosomes of macrophages, in which pH drops following particle ingestion, neutrophil phagosomes remain alkaline during the period that the oxidase is active. Until recently, their pH has been accepted to lie between 7.5 and 8. However, in a 2015 study using a probe that is more sensitive at higher pH, an average pH closer to 9 was measured in individual phagosomes (Levine AP et al. 2015).

The superoxide dismutates to hydrogen peroxide, which is used by myeloperoxidase (MPO) to generate other oxidants, including the highly microbicidal species such as hypochlorous acid (Winterbourn CC et al. 2013, 2016). View original pathway at Reactome.</div>

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Reactome-Converter 
Pathway is converted from Reactome ID: 8941413
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Shamovsky, Veronica

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Bibliography

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  1. Sharma S, Singh AK, Kaushik S, Sinha M, Singh RP, Sharma P, Sirohi H, Kaur P, Singh TP.; ''Lactoperoxidase: structural insights into the function,ligand binding and inhibition.''; PubMed Europe PMC Scholia
  2. Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Halliwell B, van der Vliet A.; ''Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils.''; PubMed Europe PMC Scholia
  3. Cape JL, Hurst JK.; ''The role of nitrite ion in phagocyte function--perspectives and puzzles.''; PubMed Europe PMC Scholia
  4. Winterbourn CC, Kettle AJ.; ''Redox reactions and microbial killing in the neutrophil phagosome.''; PubMed Europe PMC Scholia
  5. Davies MJ.; ''Myeloperoxidase-derived oxidation: mechanisms of biological damage and its prevention.''; PubMed Europe PMC Scholia
  6. Hawkins CL, Davies MJ.; ''Degradation of hyaluronic acid, poly- and monosaccharides, and model compounds by hypochlorite: evidence for radical intermediates and fragmentation.''; PubMed Europe PMC Scholia
  7. Yang Y, Bazhin AV, Werner J, Karakhanova S.; ''Reactive oxygen species in the immune system.''; PubMed Europe PMC Scholia
  8. Green JN, Chapman ALP, Bishop CJ, Winterbourn CC, Kettle AJ.; ''Neutrophil granule proteins generate bactericidal ammonia chloramine on reaction with hydrogen peroxide.''; PubMed Europe PMC Scholia
  9. Ashby MT.; ''Inorganic chemistry of defensive peroxidases in the human oral cavity.''; PubMed Europe PMC Scholia
  10. Hawkins CL, Pattison DI, Davies MJ.; ''Hypochlorite-induced oxidation of amino acids, peptides and proteins.''; PubMed Europe PMC Scholia
  11. Miyasaki KT, Zambon JJ, Jones CA, Wilson ME.; ''Role of high-avidity binding of human neutrophil myeloperoxidase in the killing of Actinobacillus actinomycetemcomitans.''; PubMed Europe PMC Scholia
  12. Bafort F, Parisi O, Perraudin JP, Jijakli MH.; ''Mode of action of lactoperoxidase as related to its antimicrobial activity: a review.''; PubMed Europe PMC Scholia
  13. Winterbourn CC, Hampton MB, Livesey JH, Kettle AJ.; ''Modeling the reactions of superoxide and myeloperoxidase in the neutrophil phagosome: implications for microbial killing.''; PubMed Europe PMC Scholia
  14. Selvaraj RJ, Zgliczynski JM, Paul BB, Sbarra AJ.; ''Enhanced killing of myeloperoxidase-coated bacteria in the myeloperoxidase-H2O2-Cl- system.''; PubMed Europe PMC Scholia
  15. Klebanoff SJ.; ''Myeloperoxidase.''; PubMed Europe PMC Scholia
  16. Rees MD, Hawkins CL, Davies MJ.; ''Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates.''; PubMed Europe PMC Scholia
  17. Peskin AV, Winterbourn CC.; ''Kinetics of the reactions of hypochlorous acid and amino acid chloramines with thiols, methionine, and ascorbate.''; PubMed Europe PMC Scholia
  18. Eiserich JP, Cross CE, Jones AD, Halliwell B, van der Vliet A.; ''Formation of nitrating and chlorinating species by reaction of nitrite with hypochlorous acid. A novel mechanism for nitric oxide-mediated protein modification.''; PubMed Europe PMC Scholia
  19. Paulsen CE, Carroll KS.; ''Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery.''; PubMed Europe PMC Scholia
  20. van den Berg JJ, Winterbourn CC, Kuypers FA.; ''Hypochlorous acid-mediated modification of cholesterol and phospholipid: analysis of reaction products by gas chromatography-mass spectrometry.''; PubMed Europe PMC Scholia
  21. Skaff O, Pattison DI, Davies MJ.; ''Hypothiocyanous acid reactivity with low-molecular-mass and protein thiols: absolute rate constants and assessment of biological relevance.''; PubMed Europe PMC Scholia
  22. Pattison DI, Davies MJ, Hawkins CL.; ''Reactions and reactivity of myeloperoxidase-derived oxidants: differential biological effects of hypochlorous and hypothiocyanous acids.''; PubMed Europe PMC Scholia
  23. Flannagan RS, Cosío G, Grinstein S.; ''Antimicrobial mechanisms of phagocytes and bacterial evasion strategies.''; PubMed Europe PMC Scholia
  24. Klebanoff SJ, Kettle AJ, Rosen H, Winterbourn CC, Nauseef WM.; ''Myeloperoxidase: a front-line defender against phagocytosed microorganisms.''; PubMed Europe PMC Scholia
  25. Winterbourn CC, Kettle AJ, Hampton MB.; ''Reactive Oxygen Species and Neutrophil Function.''; PubMed Europe PMC Scholia
  26. Fiedler TJ, Davey CA, Fenna RE.; ''X-ray crystal structure and characterization of halide-binding sites of human myeloperoxidase at 1.8 A resolution.''; PubMed Europe PMC Scholia
  27. Burner U, Furtmuller PG, Kettle AJ, Koppenol WH, Obinger C.; ''Mechanism of reaction of myeloperoxidase with nitrite.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114822view16:32, 25 January 2021ReactomeTeamReactome version 75
113267view11:33, 2 November 2020ReactomeTeamReactome version 74
112808view18:15, 9 October 2020DeSlOntology Term : 'infectious disease pathway' added !
112757view16:16, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
Cell surface R-ALL-983438 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
Cell surfaceR-ALL-983438 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
Cl-MetaboliteCHEBI:17996 (ChEBI)
Fe2+MetaboliteCHEBI:29033 (ChEBI)
GlcNAc(1-->4)MurNAc:L-Ala-gamma-D-Glu-L-Lys-(D-Ala)2 R-ALL-6788957 (Reactome)
GlcNAc-(1-->4)-MurNAc-L-Ala-gamma-D-Glu-N(6)-(beta-D-Asp)-L-Lys-(D-Ala) R-ALL-8862291 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HOCl MetaboliteCHEBI:24757 (ChEBI)
HOCl, NO2ClComplexR-ALL-6789020 (Reactome)
HOClMetaboliteCHEBI:24757 (ChEBI)
LPO ProteinP22079 (Uniprot-TrEMBL)
LPO:ferrihemeComplexR-HSA-8855484 (Reactome)
Lipid-ClR-ALL-6789104 (Reactome)
MPO (165-278) ProteinP05164 (Uniprot-TrEMBL)
MPO (279-745) ProteinP05164 (Uniprot-TrEMBL)
MPO:ferriheme:bacterial cell surfaceComplexR-HSA-6789102 (Reactome)
MPO:ferrihemeComplexR-HSA-6789030 (Reactome)
MurNAc MetaboliteCHEBI:21615 (ChEBI)
MurNAc:PeptideComplexR-ALL-6788991 (Reactome)
NO2MetaboliteCHEBI:33101 (ChEBI)
OSCN-MetaboliteCHEBI:133907 (ChEBI)
Peptide MetaboliteCHEBI:16670 (ChEBI)
Peptidyl-Cys-SClR-ALL-9625544 (Reactome)
Peptidyl-Cys-SHR-ALL-9625549 (Reactome)
Peptidyl-Cys-SHR-ALL-9626215 (Reactome)
Peptidyl-Cys-SOHR-ALL-9626211 (Reactome)
Peptidyl-Cys-SSCNR-ALL-9626213 (Reactome)
Peptidyl-Lys-NCl2R-ALL-9625918 (Reactome)
Peptidyl-Lys-NH2R-ALL-9625903 (Reactome)
Peptidyl-Lys-NHClR-ALL-9625899 (Reactome)
ROS and RNS

production in

phagocytes
PathwayR-HSA-1222556 (Reactome) The first line of defense against infectious agents involves an active recruitment of phagocytes to the site of infection. Recruited cells include polymorhonuclear (PMN) leukocytes (i.e., neutrophils) and monocytes/macrophages, which function together as innate immunity sentinels (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). Dendritic cells are also present, serving as important players in antigen presentation for ensuing adaptive responses (Savina A & Amigorena S 2007). These cell types are able to bind and engulf invading microbes into a membrane-enclosed vacuole - the phagosome, in a process termed phagocytosis. Phagocytosis can be defined as the receptor-mediated engulfment of particles greater than 0.5 micron in diameter. It is initiated by the cross-linking of host cell membrane receptors following engagement with their cognate ligands on the target surface (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). When engulfed by phagocytes, microorganisms are exposed to a number of host defense microbicidal events within the resulting phagosome. These include the production of reactive oxygen and nitrogen species (ROS and RNS, RONS) by specialized enzymes (Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013). NADPH oxidase (NOX) complex consume oxygen to produce superoxide radical anion (O2.-) and hydrogen peroxide (H2O2) (Robinson et al. 2004). Induced NO synthase (iNOS) is involved in the production of NO, which is the primary source of all RNS in biological systems (Evans TG et al. 1996). The phagocyte NADPH oxidase and iNOS are expressed in both PMN and mononuclear phagocytes and both cell types have the capacity for phagosomal burst activity. However, the magnitude of ROS generation in neutrophils far exceeds that observed in macrophages (VanderVen BC et al. 2009). Macrophages are thought to produce considerably more RNS than neutrophils (Fang FC et al. 2004; Nathan & Shiloh 2000).

The presence of RONS characterized by a relatively low reactivity, such as H2O2, O2˙− or NO, has no deleterious effect on biological environment (Attia SM 2010; Weidinger A & and Kozlov AV 2015). Their activity is controlled by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. However the relatively low reactive species can initiate a cascade of reactions to generate more damaging “secondary� species such as hydroxyl radical (•OH), singlet oxygen or peroxinitrite (Robinson JM 2008; Fang FC et al. 2004). These "secondary" RONS are extremely toxic causing irreversible damage to all classes of biomolecules (Weidinger A & and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).

Although macrophages and neutrophils use similar mechanisms for the internalization of targets, there are differences in how they perform phagocytosis and in the final outcome of the process (Tapper H & Grinstein S 1997; Vierira OV et al. 2002). Once formed, the phagosome undergoes an extensive maturation process whereby it develops into a microbicidal organelle able to eliminate the invading pathogen. Maturation involves re-modeling both the membrane of the phagosome and its luminal contents (Vierira OV et al. 2002). In macrophages, phagosome formation and maturation follows a series of strictly coordinated membrane fission/fusion events between the phagosome and compartments of the endo/lysosomal network gradually transforming the nascent phagosome into a phagolysosome, a degradative organelle endowed with potent microbicidal properties (Zimmerli S et al. 1996; Vierira OV et al. 2002). Neutrophils instead contain a large number of preformed granules such as azurophilic and specific granules that can rapidly fuse with phagosomes delivering antimicrobial substances (Karlsson A & Dahlgren C 2002; Naucler C et al. 2002; Nordenfelt P and Tapper H 2011). Phagosomal pH dynamics may also contribute to the maturation process by regulating membrane traffic events. The microbicidal activity of macrophages is characterized by progressive acidification of the lumen (down to pH 4–5) by the proton pumping vATPase. A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases reported in macrophages. Neutrophil phagosome pH regulation differs significantly from what is observed in macrophages (Nordenfelt P and Tapper H 2011; Winterbourn CC et al. 2016). The massive activation of the oxidative burst is thought to result in early alkalization of neutrophil phagosomes which is linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Other studies showed that neutrophil phagosome maintained neutral pH values before the pH gradually decreased (Jankowski A et al. 2002). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).

The Reactome module describes ROS and RNS production by phagocytic cells. The module includes cell-type specific events, for example, myeloperoxidase (MPO)-mediated production of hypochlorous acid in neutrophils. It also highlights differences between phagosomal pH dynamics in neutrophils and macrophages. The module describes microbicidal activity of selective RONS such as hydroxyl radical or peroxynitrite. However, detection of any of these species in the phagosomal environment is subject to many uncertainties (Nüsse O 2011; Erard M et al. 2018). The mechanisms by which reactive oxygen/nitrogen species kill pathogens in phagocytic immune cells are still not fully understood.

SCN(-)MetaboliteCHEBI:18022 (ChEBI)
Unsaturated lipidR-ALL-6788963 (Reactome)
betaGlcNAcMetaboliteCHEBI:28009 (ChEBI)
ferriheme b(1-) MetaboliteCHEBI:55376 (ChEBI)
nitriteMetaboliteCHEBI:16301 (ChEBI)
nitryl chloride MetaboliteCHEBI:142774 (ChEBI)
nitryl chlorideMetaboliteCHEBI:142774 (ChEBI)
peptidoglycan-NHAcComplexR-ALL-6788960 (Reactome)
peptidoglycan-chloramideComplexR-ALL-6789095 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Cell surfaceR-HSA-6789136 (Reactome)
Cl-ArrowR-HSA-9625540 (Reactome)
Cl-R-HSA-6789031 (Reactome)
Cl-R-HSA-6789126 (Reactome)
Fe2+ArrowR-HSA-6789208 (Reactome)
H+ArrowR-HSA-9625540 (Reactome)
H+R-HSA-6788974 (Reactome)
H+R-HSA-6789031 (Reactome)
H+R-HSA-6789126 (Reactome)
H+R-HSA-8933635 (Reactome)
H2O2R-HSA-6789031 (Reactome)
H2O2R-HSA-6789126 (Reactome)
H2O2R-HSA-8855490 (Reactome)
H2O2R-HSA-8933635 (Reactome)
H2OArrowR-HSA-6788974 (Reactome)
H2OArrowR-HSA-6789031 (Reactome)
H2OArrowR-HSA-6789126 (Reactome)
H2OArrowR-HSA-6789185 (Reactome)
H2OArrowR-HSA-6789218 (Reactome)
H2OArrowR-HSA-8855490 (Reactome)
H2OArrowR-HSA-8933635 (Reactome)
H2OArrowR-HSA-8941411 (Reactome)
H2OArrowR-HSA-9625548 (Reactome)
H2OArrowR-HSA-9625904 (Reactome)
H2OArrowR-HSA-9625913 (Reactome)
H2OR-HSA-9625540 (Reactome)
HOCl, NO2ClR-HSA-6789185 (Reactome)
HOCl, NO2ClR-HSA-6789218 (Reactome)
HOClArrowR-HSA-6789031 (Reactome)
HOClArrowR-HSA-6789126 (Reactome)
HOClR-HSA-6788974 (Reactome)
HOClR-HSA-9625548 (Reactome)
HOClR-HSA-9625904 (Reactome)
HOClR-HSA-9625913 (Reactome)
LPO:ferrihememim-catalysisR-HSA-8855490 (Reactome)
Lipid-ClArrowR-HSA-6789218 (Reactome)
MPO:ferriheme:bacterial cell surfaceArrowR-HSA-6789136 (Reactome)
MPO:ferriheme:bacterial cell surfacemim-catalysisR-HSA-6789031 (Reactome)
MPO:ferrihemeR-HSA-6789136 (Reactome)
MPO:ferrihememim-catalysisR-HSA-6789126 (Reactome)
MPO:ferrihememim-catalysisR-HSA-8933635 (Reactome)
MurNAc:PeptideArrowR-HSA-6789208 (Reactome)
NO2ArrowR-HSA-8933635 (Reactome)
OSCN-ArrowR-HSA-8855490 (Reactome)
OSCN-R-HSA-8941411 (Reactome)
Peptidyl-Cys-SClArrowR-HSA-9625548 (Reactome)
Peptidyl-Cys-SClR-HSA-9625540 (Reactome)
Peptidyl-Cys-SHR-HSA-8941411 (Reactome)
Peptidyl-Cys-SHR-HSA-9625548 (Reactome)
Peptidyl-Cys-SOHArrowR-HSA-9625540 (Reactome)
Peptidyl-Cys-SSCNArrowR-HSA-8941411 (Reactome)
Peptidyl-Lys-NCl2ArrowR-HSA-9625913 (Reactome)
Peptidyl-Lys-NH2R-HSA-9625904 (Reactome)
Peptidyl-Lys-NHClArrowR-HSA-9625904 (Reactome)
Peptidyl-Lys-NHClR-HSA-9625913 (Reactome)
R-HSA-6788974 (Reactome) Nitrated and chlorinated proteins were found in bacteria phagocytosed by polymorphonuclear cells, suggesting a host–defense mechanism mediated by reactive nitrogen and chlorine species (Evans TJ et al. 1996; Hazen SL et al. 1996). Hypochlorous acid (HOCl) was shown to react with nitrite NO2(-) to form nitryl chloride (NO2Cl) (Eiserich JP et al. 1996). NO2Cl formation by activated human neutrophils in the presence of added NO2(-) has been also demonstrated (Eiserich JP et al. 1998). The addition of HOCl to isolated DNA or cells in the presence of NO2(-) results in increased cytosine chlorination and DNA oxidation compared with DNA or cells in the absence ofadded NO2(-) (Whiteman M et aal. 1999; Spencer JP et al. 2000). NO2Cl was also capable of nitrating, chlorinating, and dimerizing phenolic compounds such as tyrosine (Jacob JS et al. 1996; Eiserich JP et al. 1996, 1998). These studies have emphasized the potential toxic effects of nitrite and HOCl-reaction products. However, NO2(-) has also been reported to inhibit the antimicrobial activity of HOCl and MPO (van Dalen CJ et al. 2000;Marcinkiewicz J et al. 2000).
R-HSA-6789031 (Reactome) Granule-derived cationic MPO protein can attach to negatively charged proteins and membrane epitopes of ingested bacteria (Selvaraj RJ et al. 1978; Miyasaki KT et al. 1987). This could be a way of directing HOCl for effective killing (Klebanoff SJ et al. 1999).

MPO is a heme enzyme that uses hydrogen peroxide to oxidize chloride to hypochlorous acid. MPO reacts with hydrogen peroxide, which is produced by stimulated neutrophils, to form the redox intermediate compound I (Winterbourn CC et al 2006; Davies MJ 2011; Pattison DI et al. 2012). Compound I is strongly oxidizing and reacts with a variety of substrates such as halide and pseudo-halide ions to produce hypohalous acids (HOX where X = Cl, Br, SCN). Its main physiological substrate is assumed to be chloride, which undergoes a two-electron oxidation to form hypochlorous acid (HOCl) (Winterbourn CC et al 2006; Davies MJ 2001; Pattison DI et al. 2012).

R-HSA-6789126 (Reactome) Phagosomal myeloperoxidase (MPO) is an important heme enzyme released by activated leukocytes (Klebanoff SJ & Rosen H 1978; Austin GE et al. 1994; Klebanoff S 2013). MPO protein has little bactericidal effect per se, but the enzyme-generated products are chemical oxidants that have potent antibacterial, antiviral, and antifungal properties (Pattison DI et al. 2012). Ferric MPO enzyme cycles through redox intermediates that undergo a complex array of reactions. Initial oxidation of the resting iron (III) form of the enzyme by hydrogen peroxide gives rise to a primary catalytic complex, known as Compound I (Winterbourn CC et al 2006; Davies MJ 2011; Pattison DI et al. 2012). Compound I can then undergo either two electron reduction with halide or pseudo-halide ions to form hypohalous acids (HOX where X = Cl, Br, SCN) or undergo two successive one-electron reductions, via Compound II, with consequent radical formation (the peroxidase cycle) (Winterbourn CC et al 2006; Davies MJ 2011). Due to the high reduction potentials of the Compound I and II, MPO can oxidize a variety of substrates. Chloride ion is one of the physiological substrate of MPO. Cl- undergoes a two-electron oxidation to form hypochlorous acid (HOCl) (Winterbourn CC et al 2006; Davies MJ 2001; Pattison DI et al. 2012). Studies using specific probes or biomarkers such as 3-chlorotyrosine showed that MPO reacts with H2O2 and chloride present in the phagosome to produce HOCl, and that the HOCl reacts with ingested bacteria (Jiang Q et al. 1997; Palazzolo AM et al. 2005; Kenmoku S et al. 2007; Chapman AL et al. 2002; Albrett AM et al. 2018; Degrossoli A et al. 2018). Furthermore, rapid killing of numerous organisms by isolated neutrophils has been shown to require MPO (Klebanoff SJ et al. 2013; Green JN et al. 2017). HOCl reacts readily with a range of biological molecules to form potently microbicidal products such as chloramines (Green JN et al. 2017). HOCl reacts with ROS forming toxic hydroxyl radical and singlet oxygen, however the specific role of HOCl in the microbial killing remains unclear. Modelling studies indicated that phagosomal proteins could scavenge much of the HOCl before it reaches the microbe thus limiting its ability to kill (Winterbourn CC et al. 2006).
R-HSA-6789136 (Reactome) Association of MPO with the surfaces of ingested bacteria has been observed microscopically (Selvaraj RJ et al. 1978). This could be a way of directing HOCl for effective killing (Klebanoff SJ et al. 1999). MPO has been shown to bind to the surface of a number of species (Miyasaki KT et al. 1987). However, even with MPO binding, most of the H2O2 would react with unbound MPO.
R-HSA-6789185 (Reactome) UV-visible (220-340 nm) and EPR spectroscopy monitoring of reaction of HOCl/ClO- with amides, sugars, polysaccharides, and hyaluronic acid indicate that HOCl/ClO- reacts preferentially with N-acetyl groups (Hawkins CL & Davies MJ 1998; Rees MD et al. 2003). This reaction is believed to give rise to transient chloramide (R-NCl-C(O)-R') species, which decompose rapidly to give radicals. A polymer fragmentation is thought to involve one-electron reduction of the chloramides to yield polymer-derived amidyl radicals, which subsequently undergo intramolecular hydrogen atom abstraction reactions to give carbon-centered radicals (Hawkins CL & Davies MJ 1998; Rees MD et al. 2003). The latter undergo fragmentation reactions in a site-specific manner.

The basic structure of bacterial peptidoglycan (PGN) contains a carbohydrate backbone of alternating units of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), which can be a target for HOCl -mediated oxidation (van Heijenoort J et al. 2001; Davies MJ 2011).

R-HSA-6789208 (Reactome) UV-visible (220-340 nm) and EPR spectroscopy monitoring of reaction of hypochlorite HOCl/ClO- with amides, sugars, polysaccharides, and hyaluronic acid that HOCl/ClO- reacts preferentially with N-acetyl groups (Hawkins CL & Davies MJ 1998; Rees MD et al. 2003). This reaction is believed to give rise to transient chloramide (R-NCl-C(O)-R') species, which decompose rapidly to give radicals. A polymer fragmentation is thought to involve one-electron reduction of the chloramides to yield polymer-derived amidyl radicals, which subsequently undergo intramolecular hydrogen atom abstraction reactions to give carbon-centred radicals (Hawkins CL & Davies MJ 1998; Rees MD et al. 2003). The latter undergo fragmentation reactions in a site-specific manner.

The basic structure of bacterial peptidoglycan (PGN) contains a carbohydrate backbone of alternating units of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), which can be a target for HOCl -mediated oxidation (van Heijenoort J et al. 2001; Davies MJ 2011).

R-HSA-6789218 (Reactome) HOCl reacts with the double bonds of unsaturated lipids and cholesterol to give chlorohydrins (RCH(Cl)-CH(OH)R'). Chlorohydrins, if formed in cell membranes, could cause disruption to membrane structure, since they are more polar than the parent fatty acids (Winterbourn CC et al. 1992; van den Berg JJ et al 1993).
R-HSA-8855490 (Reactome) Lactoperoxidase (LPO, also known as salivary peroxidase SPO) is a member of heme-containing peroxidase (XPO) family (Furtmüller PG et al. 2006). LPO has been identified as an antimicrobial agent within exocrine gland secretions such as milk, saliva, and tears through the oxidation of thiocyanate ion (SCN-) by hydrogen peroxide (H2O2) to yield the intermediary oxidation product hypothiocyanite ion (OSCN-), which possesses broad-spectrum of antimicrobial activity (Pruitt KM et al. 1988; Thomas EL et al. 1994; Shin K et al. 2000; Wijkstrom-Frei C et al. 2003; Tahboub YR et al. 2005; Ihalin R et al. 2006; Ashby MT 2008; Welk A et al. 2009, 2011; Bafort F et al. 2014). (OSCN-) oxidises sulphydryls of essential proteins of a microorganism, resulting in an alteration in its cellular functions (Hoogendoorn H et al. 1977; Thomas EL & Aune TM 1978; Mickelson MN 1979; Hawkins CL 2009). Functional alterations of microorganisms cause their growth inhibition and/or death. Structural studies showed that mammalian LPO functions as a monomeric single polypeptide chain which is linked to heme in the catalytic site (Singh AK et al. 2008; Sharma S et al. 2013). The dual oxidases DUOX1 and DUOX2 are the H2O2-producing isoforms of the NADPH oxidase family found in epithelial cells are thought to support LPO-mediated killing of invading pathogens (Forteza R et al. 2005; Fischer H 2009). In healthy individuals, (SCN-) is thought to originate primarily from the diet.

All the members of XPO family catalyze a similar multi-step reaction by oxidizing the heme iron in the catalitic site from Fe(III) to Fe(IV)=O and a porphyrin or aromatic side chain to a cationic radical (Furtmüller PG et al. 2006; Davies MJ et al. 2008; Gumiero A et al. 2011; Bafort F et al. 2014). The classic peroxidases catalytic cycle begins in the presence of H2O2 which reacts rapidly and reversibly with the native state of peroxidases (enzyme:Fe(III) state). Two electrons transfer from the native enzyme:Fe(III) to H2O2 generates a ferryl pi-cation-radical (E-Fe(IV)=O.+pi) intermediate named Compound I and reduces H2O2 into water. In the presence of a halogen (Cl-, Br-, or I-) or a pseudohalogen (SCN-), Compound I is reduced back to its native enzymatic form through a two-electron transfer while the (pseudo)halogen is oxidized into a hypo(pseudo)halide. Hypo(pseudo)halides are powerful oxidants with antimicrobial activity. Alternatively, Compound I is also capable of oxidizing multiple organic and inorganic molecules (AH2) by two successive sequential one-electron-transitions generating their corresponding radicals (.AH) and the peroxidase intermediate Compound II (enzyme:Fe(IV)=O) and the native enzyme:Fe(III), respectively (Furtmüller PG et al. 2006; Zederbauer M et al. 2007; Davies MJ et al. 2008; Gumiero A et al. 2011; Bafort F et al. 2014).

The Reactome event describes the halogenation cycle where LPO-derived Compound I catalyzes the oxidation of thiocyanate ion (SCN-) to hypothiocyanite ion (OSCN-).

R-HSA-8933635 (Reactome) Nitrite (NO2-) is the primary metabolic end product of nitric oxide (NO) that is produced by a wide variety of cell types by nitric oxide synthases (Knowles RG & Moncada S 1994). During inflammatory processes activated polymorphonuclear leukocytes are capable of converting physiological levels of nitrite (NO2-) into nitrogen dioxide (NO2) through the catalytic action of myeloperoxidase (MPO) (Van der Vliet A et al. 1997; Eiserich JP et al 1998; Burner U et al. 2000). Competition studies have demonstrated that MPO-dependent NO2- oxidation occurs in the presence of alternative anionic substrates (e.g. Cl-, Br, SCNT) suggesting that nitrite itself is a physiological substrate of mammalian peroxidase (Van der Vliet A et al. 1997). Nitrogen dioxide (NO2) can contribute to nitration of aromatic substrates such as tyrosine residue and 4-hydroxyphenyl acetic acid (HPA) during inflammatory processes (Sampson JB et al. 1998, Van der Vliet A et al. 1997; Eiserich JP et al 1998).

In the presence of hydrogen peroxide (H2O2) MPO can catalyze both one- and two-electron oxidations (Davies MJ 2011). Generally, ferric or native MPO reacts with H2O2 forming intemediate compound I (MPO-I). This redox intermediate is known to oxidize halides via a single two-electron reaction to produce the respective hypohalous acids and regenerate the native enzyme. Alternatively, stepwise reduction of compound I by two donor-derived electrons produces compound II (MPO-II) and subsequently the resting ferric state. Mechanistic studies have demonstrated that nitrite acts as an electron donor and reacts with compounds I to yield nitrogen dioxide (NO2) and compaund II. Subsequently, an additional nitrite molecule reduces compound II by one electron to regenerate a native state of MPO and to produce a second NO2 molecule (Burner U et al. 2000; Cape JC & Hurst JK 2009).

R-HSA-8941411 (Reactome) The reaction of hypothiocyanite (OSCN(-)) with cysteine-derived sulfhydryl groups produces sulfenyl thiocyanates (Cys-S-SCN) which in turn may form disulfides or sulfenic acids (Cys-SOH) that can then be repaired through enzymatic mechanisms (Skaff O et al. 2009; Nagy P et al. 2009; Trujillo M et a. 2015). OSCN(-) is produced by two-electron oxidation of thiocyanate (SCN(-)) in the presence of hydrogen peroxide (H2O2) (Furtmüller PG et al. 2006; Ashby MT 2008). SCN(-) oxidation is catalyzed by defensive human peroxidases, myeloperoxidase (MPO) and lactoperoxidase (LPO), occurring in human secretory mucosa, including the oral cavity, airway, and alimentary tract (Ihalin R et al. 2006; Furtmüller PG et al. 2006; Ashby MT 2008). The OSCN(-) is the conjugate base of hypothiocyanous acid (HOSCN). Both OSCN(-) and HOSCN are potent antimicrobial species that kill invading pathogens. OSCN(-)/HOSCN are thought to oxidize sulphydryls of essential proteins of a microorganism, resulting in an alteration in its cellular functions and thus regulating resident and transient flora in human secretory mucosa as part of innate immunity (Hoogendoorn H et al. 1977; Thomas EL & Aune TM 1978; Mickelson MN 1979; Hawkins CL 2009). OSCN(-)/HOSCN have been viewed as mild oxidants, which are better tolerated by host tissue (Chandler JD et al.2013; Chandler JD & Day BJ 2012). However, HOSCN may target specific thiol-containing cellular proteins resulting n the initiation of significant cellular damage (Barrett TJ & Hawkins CL 2012).
R-HSA-9625540 (Reactome) Thiol-containing cysteine (Cys) residues are reactive with species of the oxidative burst. Hypochlorous acid (HOCl) leads to chlorination of Cys residues forming Cys-sulfenic acid (Cys-SOH) intermediates, which can either form a disulfide with an adjacent thiol or be further oxidized by HOCl to generate Cys- sulfinic and Cys-sulfonic acids sequentially (Peskin AV & Winterbourn CC 2001; Hawkins CL et al. 2003; Paulsen CE & Carroll KS 2013; Winterbourn CC & Kettle AJ 2013). Disulfides function as redox switches to control protein activity and protect thiol groups against overoxidation to Cys-sulfinic and -sulfonic acids (Paulsen CE & Carroll KS 2013).
R-HSA-9625548 (Reactome) Hypochlorous acid (HOCl) is a powerful oxidant generated from H2O2 and Cl- by the heme enzyme myeloperoxidase (MPO), which is released from activated leukocytes. HOCl leads to chlorination of thiol-containing cysteine (Cys) residues forming Cys-sulfenyl chloride (Cys-SCl) intermediate and then Cys-sulfenic acid (Cys-SOH), which can either form a disulfide with an adjacent thiol or be further oxidized by HOCl to generate Cys- sulfinic and Cys-sulfonic acids sequentially (Peskin AV & Winterbourn CC 2001; Hawkins CL et al. 2003; Paulsen CE & Carroll KS 2013; Winterbourn CC & Kettle AJ 2013). Disulfides function as redox switches to control protein activity and protect thiol groups against overoxidation to Cys-sulfinic and -sulfonic acids.
R-HSA-9625904 (Reactome) Myeloperoxidase (MPO)-produced hypochlorous acid (HOCl) reacts with N-terminal amino acids and lysine (Lys) residues of proteins contained within phagosomes to form protein chloramines and dichloramines (Chapman ALP et al. 2002; Green JN et al. 2017). These species decompose to yield chlorimines, aldehydes, and the inorganic gases ammonia monochloramine (NH2Cl) and ammonia dichloramine (NHCl2) (Hazen S et al. 1998; Coker MS et al. 2008; Green JN et al. 2017). Cytotoxic NH2Cl and NHCl2 may contribute to killing of ingested bacteria (Coker MS et al. 2008; Green JN et al. 2017).
R-HSA-9625913 (Reactome) In the phagosome, hypochlorous acid (HOCl) reacts with N-terminal amino acids and lysine (Lys) residues of proteins to form protein chloramines and dichloramines (Chapman ALP et al. 2002; Green JN et al. 2017). These species decompose to yield chlorimines, aldehydes, and the inorganic gases ammonia monochloramine (NH2Cl) and ammonia dichloramine (NHCl2) (Hazen S et al. 1998; Coker MS et al. 2008; Green JN et al. 2017). Cytotoxic NH2Cl and NHCl2 may contribute to killing of ingested bacteria (Coker MS et al. 2008; Green JN et al. 2017).
SCN(-)R-HSA-8855490 (Reactome)
Unsaturated lipidR-HSA-6789218 (Reactome)
betaGlcNAcArrowR-HSA-6789208 (Reactome)
nitriteR-HSA-6788974 (Reactome)
nitriteR-HSA-8933635 (Reactome)
nitryl chlorideArrowR-HSA-6788974 (Reactome)
peptidoglycan-NHAcR-HSA-6789185 (Reactome)
peptidoglycan-chloramideArrowR-HSA-6789185 (Reactome)
peptidoglycan-chloramideR-HSA-6789208 (Reactome)

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