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

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Events associated with phagocytolytic activity of PMN cells" Organism="Homo sapiens"> <Comment Source="WikiPathways-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 &amp; 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).&lt;p&gt;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 [http://www.reactome.org/PathwayBrowser/#DIAGRAM=8941413 Reactome].</Comment> <Comment Source="Reactome-Converter">Pathway is converted from Reactome ID: 8941413</Comment> <Comment Source="Reactome-version">Reactome version: 73</Comment> <Comment Source="Reactome Author">Reactome Author: Shamovsky, Veronica</Comment> <BiopaxRef>f89</BiopaxRef> <BiopaxRef>f2d</BiopaxRef> <Attribute Key="reactome_id" Value="8941413" /> <Graphics BoardWidth="1158.0" BoardHeight="2008.0" /> <DataNode TextLabel="H2O" GraphId="a14ee" Type="Metabolite"> <Attribute Key="cellular_location" Value="phagocytic vesicle lumen" /> <Graphics CenterX="229.0" CenterY="732.0" Width="44.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15377" /> </DataNode> <DataNode TextLabel="H2O2" GraphId="a2343" Type="Metabolite"> <Attribute Key="cellular_location" Value="phagocytic vesicle lumen" /> <Graphics CenterX="307.0" CenterY="527.0" 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Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8855484" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1948.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P22079" /> </DataNode> <DataNode TextLabel="H2O" GraphId="ac2c4" Type="Metabolite"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="715.5" CenterY="103.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15377" /> </DataNode> <DataNode TextLabel="H2O" GraphId="acf15" Type="Metabolite"> <Attribute Key="cellular_location" Value="phagocytic vesicle lumen" /> <Graphics CenterX="623.0" CenterY="426.0" Width="44.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15377" /> </DataNode> <DataNode TextLabel="MPO (279-745) " GraphId="ad632" Type="Protein" GroupRef="ca37c"> <Attribute Key="cellular_location" Value="phagocytic vesicle lumen" /> <Attribute Key="complex_id" Value="R-HSA-6789030" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1308.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P05164" /> </DataNode> <DataNode TextLabel="Fe2+" GraphId="af2db" Type="Metabolite"> <Attribute Key="cellular_location" Value="phagocytic vesicle lumen" /> <Graphics CenterX="356.5" CenterY="1067.0" Width="49.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:29033" /> </DataNode> <DataNode TextLabel="Peptidyl-Cys-SH" GraphId="b5bd3"> <Attribute Key="cellular_location" Value="phagocytic vesicle lumen" /> <Graphics CenterX="759.5" CenterY="440.0" Width="113.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-ALL-9625549" /> </DataNode> <DataNode TextLabel="H2O2" GraphId="b6b91" Type="Metabolite"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="305.0" CenterY="98.0" Width="52.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:16240" /> </DataNode> <DataNode TextLabel="MurNAc:Peptide" GraphId="b6db3" Type="Complex"> <Attribute Key="cellular_location" Value="cell wall" /> <Graphics CenterX="351.5" CenterY="1128.0" Width="107.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-ALL-6788991" /> </DataNode> <DataNode TextLabel="GlcNAc-(1--&gt;4)-MurNAc-L-Ala-gamma-D-Glu-N(6)-(beta-D-Asp)-L-Lys-(D-Ala) " GraphId="b8af3" GroupRef="a7b9d"> <Attribute Key="cellular_location" Value="cell wall" /> <Attribute Key="complex_id" Value="R-ALL-6789095" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1808.0" Width="100.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-ALL-8862291" /> </DataNode> <DataNode TextLabel="SCN(-)" GraphId="bba7a" Type="Metabolite"> <Attribute Key="cellular_location" Value="extracellular region" /> <Graphics CenterX="300.0" CenterY="36.0" Width="60.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:18022" /> </DataNode> <DataNode TextLabel="ROS and RNS&#xA;production in&#xA;phagocytes" GraphId="bd8bf" Type="Pathway"> <Comment Source="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 &amp; Ozinsky A 2002; Stuart LM &amp; 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 &amp; 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 &amp; Ozinsky A 2002; Stuart LM &amp; 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 &amp; Shiloh 2000).&lt;p&gt;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 &amp; 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 “secondaryâ€� 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 &amp; and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).&lt;p&gt;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 &amp; 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 &amp; 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).&lt;p&gt;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. </Comment> <BiopaxRef>d20</BiopaxRef> <BiopaxRef>f4f</BiopaxRef> <Attribute Key="org.pathvisio.DoubleLineProperty" Value="Double" /> <Graphics CenterX="120.0" CenterY="519.0" Width="98.0" Height="58.0" ZOrder="32768" FontSize="10" Valign="Middle" LineThickness="0.0" Color="14961e" /> <Xref Database="Reactome" ID="R-HSA-1222556" /> </DataNode> <DataNode TextLabel="ferriheme b(1-) " GraphId="bfaf9" Type="Metabolite" GroupRef="d2198"> <Attribute Key="cellular_location" Value="extracellular region" /> <Attribute Key="complex_id" Value="R-HSA-8855484" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1968.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:55376" /> </DataNode> <DataNode TextLabel="Cl-" GraphId="bffee" Type="Metabolite"> <Attribute 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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.</Comment> <BiopaxRef>c03</BiopaxRef> <BiopaxRef>c12</BiopaxRef> <BiopaxRef>ac1</BiopaxRef> <BiopaxRef>d43</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="522.0" Y="602.0" /> <Point X="447.0" Y="612.0" /> <Anchor Position="0.0" Shape="None" GraphId="c01a7" /> <Anchor Position="0.99" Shape="None" GraphId="f1828" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789136" /> </Interaction> <Interaction GraphId="a9230"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="256.0" Y="638.0" GraphRef="c075f" RelX="1.0" RelY="0.0" /> <Point X="276.0" Y="655.0" GraphRef="e1839" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789031" /> </Interaction> <Interaction GraphId="aad6f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="419.0" Y="783.0" GraphRef="c5972" RelX="-1.0" RelY="0.0" 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<Point X="276.0" Y="676.0" GraphRef="abd35" RelX="0.0" RelY="-1.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789031" /> </Interaction> <Interaction GraphId="b6ec9"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="425.0" Y="863.0" GraphRef="b6e15" RelX="-0.009999999999990905" RelY="0.4199999999999591" /> <Point X="454.0" Y="884.0" GraphRef="d983c" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789218" /> </Interaction> <Interaction GraphId="b79c8"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="392.0" Y="311.0" GraphRef="ebcfd" RelX="1.0" RelY="0.0" /> <Point X="657.0" Y="345.0" GraphRef="b88fb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6788974" /> </Interaction> <Interaction GraphId="b9ad2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="562.0" Y="404.0" GraphRef="cf3e3" RelX="0.5" RelY="0.0" /> <Point X="629.0" Y="390.0" GraphRef="c001f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789126" /> </Interaction> <Interaction GraphId="b9f39"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="831.0" Y="411.0" GraphRef="c0389" RelX="0.5299999999999727" RelY="0.009999999999990905" /> <Point X="846.0" Y="393.0" GraphRef="f2b50" RelX="0.0" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625548" /> </Interaction> <Interaction GraphId="ba7a0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="501.0" Y="517.0" GraphRef="a5dc2" RelX="-1.0" RelY="0.0" /> <Point X="529.0" Y="464.0" GraphRef="d34fb" RelX="40.5" RelY="27.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8933635" /> </Interaction> <Interaction GraphId="bb309"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="653.0" Y="375.0" GraphRef="c001f" RelX="-0.02040816326530612" RelY="-1.0" /> <Point X="657.0" Y="345.0" GraphRef="b88fb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6788974" /> </Interaction> <Interaction GraphId="bb8ce"> <Comment Source="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).</Comment> <BiopaxRef>d6d</BiopaxRef> <BiopaxRef>eb1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="657.0" Y="345.0" /> <Point X="775.0" Y="345.0" /> <Anchor Position="0.0" Shape="None" GraphId="b88fb" /> <Anchor Position="0.99" Shape="None" GraphId="bbe48" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6788974" /> </Interaction> <Interaction GraphId="bb95f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="656.0" Y="74.0" GraphRef="c16de" RelX="0.42999999999995" RelY="0.0" /> <Point X="695.0" Y="103.0" GraphRef="ac2c4" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8941411" /> </Interaction> <Interaction GraphId="bcecf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="846.0" Y="393.0" GraphRef="f2b50" RelX="0.0" RelY="1.0" /> <Point X="867.0" Y="411.0" GraphRef="e49e2" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625540" /> </Interaction> <Interaction GraphId="bd690"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="759.0" Y="429.0" GraphRef="b5bd3" RelX="-0.008849557522123894" RelY="-1.0" /> <Point X="778.0" Y="410.0" GraphRef="e4cee" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625548" /> </Interaction> <Interaction GraphId="c0c81"> <Comment Source="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 &amp; 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).&lt;p&gt;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 &amp; Hurst JK 2009).</Comment> <BiopaxRef>cc0</BiopaxRef> <BiopaxRef>dba</BiopaxRef> <BiopaxRef>a5a</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="413.0" Y="408.0" /> <Point X="564.0" Y="465.0" /> <Anchor Position="0.0" Shape="None" GraphId="f70ba" /> <Anchor Position="0.99" Shape="None" GraphId="fbfa9" /> <Anchor Position="0.5" Shape="None" GraphId="d34fb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8933635" /> </Interaction> <Interaction GraphId="c2a61"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="545.0" Y="625.0" GraphRef="fcfc1" RelX="0.0" RelY="-1.0" /> <Point X="522.0" Y="602.0" GraphRef="c01a7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789136" /> </Interaction> <Interaction GraphId="c3e40"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="408.0" Y="1108.0" GraphRef="b8892" RelX="0.009999999999990905" RelY="0.6099999999999" /> <Point X="404.0" Y="1128.0" GraphRef="b6db3" RelX="0.9813084112149533" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789208" /> </Interaction> <Interaction GraphId="c6096"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="775.0" Y="345.0" GraphRef="bbe48" RelX="1.1800000000000637" RelY="0.0" /> <Point X="824.0" Y="378.0" GraphRef="f2b50" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6788974" /> </Interaction> <Interaction GraphId="c6332"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="307.0" Y="542.0" GraphRef="a2343" RelX="0.0" RelY="1.0" /> <Point X="276.0" Y="655.0" GraphRef="e1839" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789031" /> </Interaction> <Interaction GraphId="cd5fc"> <Comment Source="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).</Comment> <BiopaxRef>f5e</BiopaxRef> <BiopaxRef>ff7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="697.0" Y="545.0" /> <Point X="741.0" Y="544.0" /> <Anchor Position="0.0" Shape="None" GraphId="ec2f3" /> <Anchor Position="0.99" Shape="None" GraphId="b227e" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625904" /> </Interaction> <Interaction GraphId="cec16"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="564.0" Y="465.0" GraphRef="fbfa9" RelX="1.509999999999991" RelY="0.5699999999999932" /> <Point X="608.0" Y="505.0" GraphRef="c094a" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8933635" /> </Interaction> <Interaction GraphId="cfc38"> <Comment Source="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).</Comment> <BiopaxRef>f5e</BiopaxRef> <BiopaxRef>ff7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="877.0" Y="545.0" /> <Point X="925.0" Y="545.0" /> <Anchor Position="0.0" Shape="None" GraphId="f7252" /> <Anchor Position="0.99" Shape="None" GraphId="f274c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625913" /> </Interaction> <Interaction GraphId="d1069"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="741.0" Y="544.0" GraphRef="b227e" RelX="0.44000000000005457" RelY="-0.009999999999990905" /> <Point X="771.0" Y="531.0" GraphRef="fa3b5" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625904" /> </Interaction> <Interaction GraphId="d2eca"> <Comment Source="Reactome">Phagosomal myeloperoxidase (MPO) is an important heme enzyme released by activated leukocytes (Klebanoff SJ &amp; 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). </Comment> <BiopaxRef>cf7</BiopaxRef> <BiopaxRef>a5a</BiopaxRef> <BiopaxRef>e59</BiopaxRef> <BiopaxRef>d43</BiopaxRef> <BiopaxRef>d88</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="512.0" Y="404.0" /> <Point X="562.0" Y="404.0" /> <Anchor Position="0.0" Shape="None" GraphId="a019e" /> <Anchor Position="0.99" Shape="None" GraphId="cf3e3" /> <Anchor Position="0.5" Shape="None" GraphId="f1b46" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789126" /> </Interaction> <Interaction GraphId="d333b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="380.0" Y="1067.0" GraphRef="af2db" RelX="0.9591836734693877" RelY="0.0" /> <Point X="409.0" Y="1069.0" GraphRef="aeb63" RelX="1.5" RelY="-8.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789208" /> </Interaction> <Interaction GraphId="d47a2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="656.0" Y="74.0" GraphRef="c16de" RelX="0.42999999999995" RelY="0.0" /> <Point X="662.0" Y="29.0" GraphRef="f07f7" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8941411" /> </Interaction> <Interaction GraphId="d4ecf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="603.0" Y="40.0" GraphRef="f9adf" RelX="-0.010101010101010102" RelY="1.0" /> <Point X="613.0" Y="74.0" GraphRef="fa3b6" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8941411" /> </Interaction> <Interaction GraphId="d70c3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="453.0" Y="63.0" GraphRef="ed73c" RelX="0.9900000000000091" RelY="0.00999999999999801" /> <Point X="471.0" Y="43.0" GraphRef="cc91c" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8855490" /> </Interaction> <Interaction GraphId="da069"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="552.0" Y="506.0" GraphRef="a5dc2" RelX="0.0" RelY="-1.0" /> <Point X="537.0" Y="404.0" GraphRef="f1b46" RelX="0.0" RelY="0.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789126" /> </Interaction> <Interaction GraphId="db548"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="333.0" Y="1003.0" GraphRef="abc98" RelX="0.0" RelY="0.38999999999998636" /> <Point X="358.0" Y="1023.0" GraphRef="df54b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789185" /> </Interaction> <Interaction GraphId="dba54"> <Comment Source="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 &amp; Winterbourn CC 2001; Hawkins CL et al. 2003; Paulsen CE &amp; Carroll KS 2013; Winterbourn CC &amp; Kettle AJ 2013). Disulfides function as redox switches to control protein activity and protect thiol groups against overoxidation to Cys-sulfinic and -sulfonic acids.</Comment> <BiopaxRef>f5e</BiopaxRef> <BiopaxRef>f2d</BiopaxRef> <BiopaxRef>af8</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="778.0" Y="410.0" /> <Point X="831.0" Y="411.0" /> <Anchor Position="0.0" Shape="None" GraphId="e4cee" /> <Anchor Position="0.99" Shape="None" GraphId="c0389" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625548" /> </Interaction> <Interaction GraphId="dbdf2"> <Comment Source="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 &amp; 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 &amp; Davies MJ 1998; Rees MD et al. 2003). The latter undergo fragmentation reactions in a site-specific manner.&lt;p&gt;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).</Comment> <BiopaxRef>d9e</BiopaxRef> <BiopaxRef>eb1</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="333.0" Y="964.0" /> <Point X="333.0" Y="1003.0" /> <Anchor Position="0.0" Shape="None" GraphId="a8ff9" /> <Anchor Position="0.99" Shape="None" GraphId="abc98" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789185" /> </Interaction> <Interaction GraphId="dd9db"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="408.0" Y="1108.0" GraphRef="b8892" RelX="0.009999999999990905" RelY="0.6099999999999" /> <Point X="411.0" Y="1169.0" GraphRef="dbe18" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789208" /> </Interaction> <Interaction GraphId="de8a5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="362.0" Y="26.0" GraphRef="c0912" RelX="-1.0" RelY="0.0" /> <Point X="414.0" Y="62.0" GraphRef="b5bd9" RelX="10.5" RelY="-0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8855490" /> </Interaction> <Interaction GraphId="debb6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="276.0" Y="700.0" GraphRef="ba817" RelX="0.0" RelY="0.4500000000000455" /> <Point X="251.0" Y="732.0" GraphRef="a14ee" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789031" /> </Interaction> <Interaction GraphId="e024e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="925.0" Y="545.0" GraphRef="f274c" RelX="0.4800000000000182" RelY="0.0" /> <Point X="902.0" Y="573.0" GraphRef="dba2a" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625913" /> </Interaction> <Interaction GraphId="e0ca0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="284.0" Y="343.0" GraphRef="a5418" RelX="0.9459459459459459" RelY="0.0" /> <Point X="657.0" Y="345.0" GraphRef="b88fb" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6788974" /> </Interaction> <Interaction GraphId="e1de0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="333.0" Y="1003.0" GraphRef="abc98" RelX="0.0" RelY="0.38999999999998636" /> <Point X="307.0" Y="1023.0" GraphRef="d6232" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789185" /> </Interaction> <Interaction GraphId="e275e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="775.0" Y="345.0" GraphRef="bbe48" RelX="1.1800000000000637" RelY="0.0" /> <Point X="868.0" Y="345.0" GraphRef="d7bd1" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6788974" /> </Interaction> <Interaction GraphId="e3f15"> <Comment Source="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).&lt;p&gt;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).&lt;br&gt;</Comment> <BiopaxRef>d43</BiopaxRef> <BiopaxRef>cf7</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="276.0" Y="655.0" /> <Point X="276.0" Y="700.0" /> <Anchor Position="0.0" Shape="None" GraphId="e1839" /> <Anchor Position="0.99" Shape="None" GraphId="ba817" /> <Anchor Position="0.5" Shape="None" GraphId="abd35" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789031" /> </Interaction> <Interaction GraphId="e3fdd"> <Comment Source="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).</Comment> <BiopaxRef>c3b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="426.0" Y="821.0" /> <Point X="425.0" Y="863.0" /> <Anchor Position="0.0" Shape="None" GraphId="b2e25" /> <Anchor Position="0.99" Shape="None" GraphId="b6e15" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789218" /> </Interaction> <Interaction GraphId="e4107"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="562.0" Y="404.0" GraphRef="cf3e3" RelX="0.5" RelY="0.0" /> <Point X="601.0" Y="426.0" GraphRef="acf15" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789126" /> </Interaction> <Interaction GraphId="e4933"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="914.0" Y="411.0" GraphRef="e358b" RelX="0.4700000000000273" RelY="0.0" /> <Point X="975.0" Y="423.0" GraphRef="bffee" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625540" /> </Interaction> <Interaction GraphId="e4eca"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="266.0" Y="358.0" GraphRef="a5418" RelX="-0.02702702702702703" RelY="1.0" /> <Point X="276.0" Y="655.0" GraphRef="e1839" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789031" /> </Interaction> <Interaction GraphId="e53c2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="710.0" Y="572.0" GraphRef="cf14c" RelX="0.9834710743801653" RelY="0.0" /> <Point X="697.0" Y="545.0" GraphRef="ec2f3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625904" /> </Interaction> <Interaction GraphId="e6872"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="447.0" Y="612.0" GraphRef="f1828" RelX="-0.75" RelY="0.10000000000002274" /> <Point X="444.0" Y="625.0" GraphRef="fba2a" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789136" /> </Interaction> <Interaction GraphId="e780b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="564.0" Y="465.0" GraphRef="fbfa9" RelX="1.509999999999991" RelY="0.5699999999999932" /> <Point X="601.0" Y="426.0" GraphRef="acf15" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8933635" /> </Interaction> <Interaction GraphId="e7f65"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="425.0" Y="863.0" GraphRef="b6e15" RelX="-0.009999999999990905" RelY="0.4199999999999591" /> <Point X="384.0" Y="872.0" GraphRef="e85c0" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789218" /> </Interaction> <Interaction GraphId="e88a3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="334.0" Y="798.0" GraphRef="d2b20" RelX="0.9775280898876404" RelY="0.0" /> <Point X="426.0" Y="821.0" GraphRef="b2e25" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-6789218" /> </Interaction> <Interaction GraphId="edaff"> <Comment Source="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 &amp; 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 &amp; Day BJ 2012). However, HOSCN may target specific thiol-containing cellular proteins resulting n the initiation of significant cellular damage (Barrett TJ &amp; Hawkins CL 2012). </Comment> <BiopaxRef>eae</BiopaxRef> <BiopaxRef>b33</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="613.0" Y="74.0" /> <Point X="656.0" Y="74.0" /> <Anchor Position="0.0" Shape="None" GraphId="fa3b6" /> <Anchor Position="0.99" Shape="None" GraphId="c16de" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8941411" /> </Interaction> <Interaction GraphId="eed39"> <Comment Source="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 &amp; 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.&lt;p&gt;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).&lt;p&gt;The Reactome event describes the halogenation cycle where LPO-derived Compound I catalyzes the oxidation of thiocyanate ion (SCN-) to hypothiocyanite ion (OSCN-).</Comment> <BiopaxRef>b86</BiopaxRef> <BiopaxRef>c01</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="354.0" Y="62.0" /> <Point X="453.0" Y="63.0" /> <Anchor Position="0.0" Shape="None" GraphId="b681f" /> <Anchor Position="0.99" Shape="None" GraphId="ed73c" /> <Anchor Position="0.5" Shape="None" GraphId="b5bd9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8855490" /> </Interaction> <Interaction GraphId="f145d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="653.0" Y="405.0" GraphRef="c001f" RelX="-0.02040816326530612" RelY="1.0" /> <Point X="697.0" Y="545.0" GraphRef="ec2f3" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-9625904" /> </Interaction> <Interaction GraphId="f1829"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="330.0" Y="36.0" GraphRef="bba7a" RelX="1.0" RelY="0.0" /> <Point X="354.0" Y="62.0" GraphRef="b681f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-8855490" /> </Interaction> <Interaction GraphId="f31a3"> <Comment Source="Reactome">Thiol-containing cysteine (Cys) residues are reactive with species of the oxidative burst. 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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 &amp; Davies MJ 1998; Rees MD et al. 2003). 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rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Halliwell B, van der Vliet A.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="f89"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">27050287</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Reactive Oxygen Species and Neutrophil Function.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Winterbourn CC, Kettle AJ, Hampton MB.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="fb9"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">15078224</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Hypochlorite and superoxide radicals can act synergistically to induce fragmentation of hyaluronan and chondroitin sulphates.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Rees MD, Hawkins CL, Davies MJ.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="b33"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">18809743</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Inorganic chemistry of defensive peroxidases in the human oral 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