BioPAX pathway converted from "Metal sequestration by antimicrobial proteins" in the Reactome database.Metal sequestration by antimicrobial proteinsMetal sequestration by antimicrobial proteinsThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>S100A8:S100A9 binds Mn2+S100A8:S100A9 binds Mn2+This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 2660992extracellular regionGO0005576manganese(2+) [ChEBI:29035]manganese(2+)manganese(II)manganous ionMANGANESE (II) IONmanganese, ion (Mn2+)Mn(2+)Reactomehttp://www.reactome.orgChEBI29035Reactome DB_ID: 741132sodium(1+) [ChEBI:29101]sodium(1+)ChEBI29101Reactome DB_ID: 97953731S100A8:S100A9:Ca2+ [extracellular region]S100A8:S100A9:Ca2+Reactome DB_ID: 741124calcium(2+) [ChEBI:29108]calcium(2+)ChEBI29108Reactome DB_ID: 97830872S100A8:S100A9 [extracellular region]S100A8:S100A9Reactome DB_ID: 97830851UniProt:P31725S100a9Mus musculusNCBI Taxonomy10090UniProtP31725Chain Coordinates2EQUAL114EQUALReactome DB_ID: 97830811UniProt:P27005S100a8UniProtP270051EQUAL93EQUALReactome Database ID Release 759783087Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9783087ReactomeR-MMU-54328341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5432834.1Reactome Database ID Release 759795373Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9795373ReactomeR-MMU-89441981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8944198.1Reactome DB_ID: 97953791S100A8:S100A9:Ca2+:Mn2+:Na+ [extracellular region]S100A8:S100A9:Ca2+:Mn2+:Na+Reactome DB_ID: 741132Reactome DB_ID: 2660992Reactome DB_ID: 97953731Reactome Database ID Release 759795379Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9795379ReactomeR-MMU-67984111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6798411.1Reactome Database ID Release 759795381Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9795381ReactomeR-MMU-67985281Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6798528.1S100A8 and S100A9 are calcium-binding regulators of inflammatory processes and immune response (also know as migration inhibitory factor-related proteins 8 (MRP8) and MRP14). S100A8 & S100A9 are constitutively expressed in neutrophils, myeloid-derived dendritic cells, platelets, osteoclasts and hypertrophic chondrocytes (Hessian PA et al. 1993; Kumar A et al. 2003; Healy AM et al. 2006; Schelbergen RF et al 2012). In contrast, these molecules are induced under inflammatory stimuli in monocytes/macrophages, microvascular endothelial cells, keratinocytes and fibroblasts (Hessian PA et al. 1993; Eckert RL et al. 2004; Viemann D et al. 2005; McCormick MM et al. 2005; Hsu K et al. 2005). S100A8 & S100A9 are known to have diverse functions including antimicrobial activities. During infectious processes S100A8 and S100A9 are delivered to the tissue abscess by recruited neutrophils. S100A8 & S100A9 exist mainly as a S100A8:S100A9 heterodimer which is termed calprotectin based on its role in innate immunity (Korndorfer IP et al. 2007). Calprotectin inhibits bacterial growth through chelation of extracellular manganese Mn(2+), zinc Zn(2+) and possibly iron Fe(2+) and thus restricts metal-ion availability during infection (Damo SM et al. 2013; Brophy MB et al. 2012, 2013; Hayden JA et al. 2013; Gagnon DM et al. 2015; Nakashige TG et al. 2015). Calprotectin exhibited antimicrobial activity for a broad range of Gram-positive and Gram-negative bacterial pathogens including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis, Enterococcus faecalis, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Shigella flexneri and Acinetobacter baumannii (Damo SM et al. 2013; Kehl-Fie TE et al. 2011; Nakashige TG et al. 2015). <p>Both S100A8 and S100A9 belong to the S100 family of helix-turn-helix (EF-hand) calcium Ca(2+)-binding proteins. S100 proteins are involved in a wide range of cellular functions (Donato R et al. 2013; Zackular JP et al. 2015; Vogl et al. 2007). Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca(2+) homeostasis, inflammation and migration/invasion (Donato R et al. 2013). During infection, certain S100 proteins can be secreted or released by cells to act as damage-associated molecular patterns (DAMPs) and interact with pattern recognition receptors to modulate inflammatory responses (Foell D et al. 2007; Vogl et al. 2007). In addition, these inflammatory S100 proteins have antimicrobial function by sequestering essential transition metals from bacteria, preventing their growth (Zackular JP et al. 2015). The fundamental structural unit of S100 proteins is a highly integrated antiparallel dimer (Potts BC et al. 1995; Heizmann CW et al. 2002; Brodersen DE et al. 1999; Moroz OV et al. 2009; Gagnon DM et al. 2015). All S100 proteins form this structure as homodimers. S100A8 and S100A9 are unique among all members of the S100 family because they preferentially form a heterodimer. Calprotectin (S100A8:S100A9) and other S100 proteins are Ca(2+)-activated regulators (Brophy MB et al. 2012; Donato R et al. 2013). Inside the cell, where the basal level of Ca(2+) is in the nanomolar range, S100 proteins can serve as a sensor of Ca(2+)-mediated signals. In the extracellular milieu, S100 proteins are perpetually (Ca2+)-bound because Ca(2+) concentration is in the millimolar range. Ca(2+) is also known to stimulate formation of higher order oligomers of S100 proteins, including S100A8/S100A9 tetramers (Leukert N et al. 2006; Korndörfer IP et al. 2007). Upon dimerization S100A8 and S100A9 form two metal binding sites at the dimer interface, both of which can bind to Zn(2+) with high affinity (Kd Zn(2+) about 10e-9 M) (Damo SM et al. 2013; Brophy MB et al. 2013). A chelation of Mn(2+) involves a single binding site (Kd Mn(2+) around 10e-7 - 10e-8 M) (Damo SM et al. 2013; Hayden JA et al. 2013; Gagnon DM et al. 2015).<p> Thus, calprotectin S100A8:S100A9 inhibits bacterial growth by targeting transition metals and sequestering these metals in a process referred to as nutritional immunity.8445331Pubmed1993MRP-8 and MRP-14, two abundant Ca(2+)-binding proteins of neutrophils and monocytesHessian, P AEdgeworth, JHogg, NJ. Leukoc. Biol. 53:197-20416690079Pubmed2006Calcium-dependent tetramer formation of S100A8 and S100A9 is essential for biological activityLeukert, NadjaVogl, ThomasStrupat, KerstinReichelt, RudolfSorg, ClemensRoth, JohannesJ. Mol. Biol. 359:961-7216216873Pubmed2005S100A8 and S100A9 in human arterial wall. Implications for atherogenesisMcCormick, Michelle MRahimi, FaridBobryshev, Yuri VGaus, KatharinaZreiqat, HalaCai, HongLord, Reginald S AGeczy, Carolyn LJ. Biol. Chem. 280:41521-910026247Pubmed1999Zinc-binding site of an S100 protein revealed. Two crystal structures of Ca2+-bound human psoriasin (S100A7) in the Zn2+-loaded and Zn2+-free statesBrodersen, D ENyborg, JKjeldgaard, MBiochemistry 38:1695-70423082970Pubmed2012Calcium ion gradients modulate the zinc affinity and antibacterial activity of human calprotectinBrophy, Megan BrunjesHayden, Joshua ANolan, Elizabeth MJ. Am. Chem. Soc. 134:18089-10024245608Pubmed2013Contributions of the S100A9 C-terminal tail to high-affinity Mn(II) chelation by the host-defense protein human calprotectinBrophy, Megan BrunjesNakashige, Toshiki GGaillard, AlethNolan, Elizabeth MJ. Am. Chem. Soc. 135:17804-1711991838Pubmed2002S100 proteins: structure, functions and pathologyHeizmann, CWFritz, GünterSchäfer, Beat WFront. Biosci. 7:d1356-6822834835Pubmed2013Functions of S100 proteinsDonato, RCannon, B RSorci, GRiuzzi, FHsu, KWeber, D JGeczy, C LCurr. Mol. Med. 13:24-5725597447Pubmed2015Manganese binding properties of human calprotectin under conditions of high and low calcium: X-ray crystallographic and advanced electron paramagnetic resonance spectroscopic analysisGagnon, Derek MBrophy, Megan BrunjesBowman, Sarah E JStich, Troy ADrennan, Catherine LBritt, R DavidNolan, Elizabeth MJ. Am. Chem. Soc. 137:3004-1615598812Pubmed2005Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cellsViemann, DorotheeStrey, AnkeJanning, AnnetteJurk, KerstinKlimmek, KerstinVogl, ThomasHirono, KeiichiIchida, FukikoFoell, DirkKehrel, BeateGerke, VolkerSorg, ClemensRoth, JohannesBlood 105:2955-6215191538Pubmed2004S100 proteins in the epidermisEckert, Richard LBroome, Ann-MarieRuse, MonicaRobinson, NancyRyan, DLee, KathleenJ. Invest. Dermatol. 123:23-3319386136Pubmed2009Both Ca2+ and Zn2+ are essential for S100A12 protein oligomerization and functionMoroz, Olga VBurkitt, WillWittkowski, HelmutHe, WeiIanoul, AnatoliNovitskaya, VeraXie, JingjingPolyakova, OxanaLednev, Igor KShekhtman, AlexanderDerrick, Peter JBjoerk, PerFoell, DirkBronstein, Igor BBMC Biochem. 10:1115699168Pubmed2005Regulation of S100A8 by glucocorticoidsHsu, KennethPassey, Robert JEndoh, YasumiRahimi, FaridYoussef, PeterYen, TinaGeczy, Carolyn LJ. Immunol. 174:2318-2614555857Pubmed2003Interleukin-10 influences the expression of MRP8 and MRP14 in human dendritic cellsKumar, AnitaSteinkasserer, AlexanderBerchtold, SusanneInt. Arch. Allergy Immunol. 132:40-722127564Pubmed2012Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4Schelbergen, Rik F PBlom, Arjen Bvan den Bosch, Martijn H JSlöetjes, AnnetAbdollahi-Roodsaz, ShahlaSchreurs, B WimMort, John SVogl, ThomasRoth, Johannesvan den Berg, Wim Bvan Lent, Peter L E MArthritis Rheum. 64:1477-8717767165Pubmed2007Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shockVogl, ThomasTenbrock, KlausLudwig, StephanLeukert, NadjaEhrhardt, Christinavan Zoelen, Marieke A DNacken, WolfgangFoell, Dirkvan der Poll, TomSorg, ClemensRoth, JohannesNat. Med. 13:1042-921843872Pubmed2011Nutrient metal sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil killing of Staphylococcus aureusKehl-Fie, Thomas EChitayat, SethHood, M IndriatiDamo, StevenRestrepo, NicoleGarcia, CarlosMunro, Kim AChazin, Walter JSkaar, Eric PCell Host Microbe 10:158-647552751Pubmed1995The structure of calcyclin reveals a novel homodimeric fold for S100 Ca(2+)-binding proteinsPotts, B CSmith, JAkke, MMacke, T JOkazaki, KHidaka, HCase, D AChazin, W JNat. Struct. Biol. 2:790-623276281Pubmed2013High-affinity manganese coordination by human calprotectin is calcium-dependent and requires the histidine-rich site formed at the dimer interfaceHayden, Joshua ABrophy, Megan BrunjesCunden, Lisa SNolan, Elizabeth MJ. Am. Chem. Soc. 135:775-8716682612Pubmed2006Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular eventsHealy, Aileen MPickard, Michael DPradhan, Aruna DWang, YunmeiChen, ZhipingCroce, KevinSakuma, MasashiShi, CanZago, Alexandre CGarasic, JosephDamokosh, Andrew IDowie, Tracy LPoisson, LouisLillie, JamesLibby, PeterRidker, Paul MSimon, Daniel ICirculation 113:2278-8423431180Pubmed2013Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogensDamo, Steven MKehl-Fie, Thomas ESugitani, NorieHolt, Marilyn ERathi, SubodhMurphy, Wesley JZhang, YaofangBetz, ChristineHench, LauraFritz, GünterSkaar, Eric PChazin, Walter JProc. Natl. Acad. Sci. U.S.A. 110:3841-626302479Pubmed2015Human calprotectin is an iron-sequestering host-defense proteinNakashige, Toshiki GZhang, BoKrebs, CarstenNolan, Elizabeth MNat. Chem. Biol. 11:765-7117553524Pubmed2007The crystal structure of the human (S100A8/S100A9)2 heterotetramer, calprotectin, illustrates how conformational changes of interacting alpha-helices can determine specific association of two EF-hand proteinsKorndörfer, Ingo PBrueckner, FlorianSkerra, ArneJ. Mol. Biol. 370:887-9826055713Pubmed2015Nutritional Immunity: S100 Proteins at the Host-Pathogen InterfaceZackular, Joseph PChazin, Walter JSkaar, Eric PJ. Biol. Chem. 290:18991-8inferred by electronic annotationIEAGOIEAS100A8:S100A9 binds Zn2+S100A8:S100A9 binds Zn2+This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 1584174zinc(2+) [ChEBI:29105]zinc(2+)ChEBI29105Reactome DB_ID: 97953731Reactome DB_ID: 97953751S100A8:S100A9:Ca2+:Zn2+ [extracellular region]S100A8:S100A9:Ca2+:Zn2+Reactome DB_ID: 1584174Reactome DB_ID: 741124Reactome DB_ID: 97830872Reactome Database ID Release 759795375Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9795375ReactomeR-MMU-89441891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-8944189.1Reactome Database ID Release 759795377Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9795377ReactomeR-MMU-67984741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6798474.1Two members of the S100 protein family, S100A8 (also know as migration inhibitory factor-related proteins 8 (MRP8)) and S100A9 (MRP14) are calcium-binding regulators of inflammatory processes and immune response. S100A8 & S100A9 are constitutively expressed in neutrophils, myeloid-derived dendritic cells, platelets, osteoclasts and hypertrophic chondrocytes (Hessian PA et al. 1993; Kumar A et al. 2003; Healy AM et al. 2006; Schelbergen RF et al 2012). In contrast, these molecules are induced under inflammatory stimuli in monocytes/macrophages, microvascular endothelial cells, keratinocytes and fibroblasts (Hessian PA et al. 1993; Eckert RL et al. 2004; Viemann D et al. 2005; McCormick MM et al. 2005; Hsu K et al. 2005). S100A8 & S100A9 are known to have diverse functions including antimicrobial activities. During infectious processes S100A8 and S100A9 are delivered to the tissue abscess by recruited neutrophils. S100A8 & S100A9 exist mainly as a S100A8:S100A9 heterodimer which is termed calprotectin based on its role in innate immunity (Korndorfer IP et al. 2007). Calprotectin inhibits bacterial growth through chelation of extracellular manganese Mn(2+), zinc Zn(2+) and possibly iron Fe(2+) and thus restricts metal-ion availability during infection (Damo SM et al. 2013; Brophy MB et al. 2012, 2013; Hayden JA et al. 2013; Gagnon DM et al. 2015; Nakashige TG et al. 2015). Calprotectin exhibited antimicrobial activity for a broad range of Gram-positive and Gram-negative bacterial pathogens including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis, Enterococcus faecalis, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Shigella flexneri and Acinetobacter baumannii (Damo SM et al. 2013; Kehl-Fie TE et al. 2011; Nakashige TG et al. 2015). <p>Both S100A8 and S100A9 belong to the S100 family of helix-turn-helix (EF-hand) calcium Ca(2+)-binding proteins. S100 proteins are involved in a wide range of cellular functions (Donato R et al. 2013; Zackular JP et al. 2015; Vogl et al. 2007). Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca(2+) homeostasis, inflammation and migration/invasion (Donato R et al. 2013). During infection, certain S100 proteins can be secreted or released by cells to act as damage-associated molecular patterns (DAMPs) and interact with pattern recognition receptors to modulate inflammatory responses (Foell D et al. 2007; Vogl et al. 2007). In addition, these inflammatory S100 proteins have antimicrobial function by sequestering essential transition metals from bacteria, preventing their growth (Zackular JP et al. 2015). The fundamental structural unit of S100 proteins is a highly integrated antiparallel dimer (Potts BC et al. 1995; Heizmann CW et al. 2002; Brodersen DE et al. 1999; Moroz OV et al. 2009; Gagnon DM et al. 2015). All S100 proteins form this structure as homodimers. S100A8 and S100A9 are unique among all members of the S100 family because they preferentially form a heterodimer. Calprotectin (S100A8:S100A9) and other S100 proteins are Ca(2+)-activated regulators (Brophy MB et al. 2012; Donato R et al. 2013). Inside the cell, where the basal level of Ca(2+) is in the nanomolar range, S100 proteins can serve as a sensor of Ca(2+)-mediated signals. In the extracellular milieu, S100 proteins are perpetually (Ca2+)-bound because Ca(2+) concentration is in the millimolar range. Ca(2+) is also known to stimulate formation of higher order oligomers of S100 proteins, including S100A8/S100A9 tetramers (Leukert N et al. 2006; Korndörfer IP et al. 2007). Upon dimerization S100A8 and S100A9 form two metal binding sites at the dimer interface, both of which can bind to Zn(2+) with high affinity (Kd Zn(2+) about 10e-9 M) (Damo SM et al. 2013; Brophy MB et al. 2013). A chelation of Mn(2+) involves a single binding site (Kd Mn(2+) around 10e-7 - 10e-8 M) (Damo SM et al. 2013; Hayden JA et al. 2013; Gagnon DM et al. 2015).<p> Thus, calprotectin S100A8:S100A9 inhibits bacterial growth by targeting transition metals and sequestering these metals in a process referred to as nutritional immunity.inferred by electronic annotationIEAGOIEALactoferrin scavenges iron ionsLactoferrin scavenges iron ionsThis event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 12226112phagocytic vesicle lumenGO0097013iron(3+) [ChEBI:29034]iron(3+)Ferric ionferric ironiron, ion (Fe(3+))Fe3+FE (III) IONFe(III)Fe(3+)ChEBI29034Reactome DB_ID: 97545401UniProt:P08071LtfUniProtP0807120EQUAL710EQUALReactome DB_ID: 21010512carbonate [ChEBI:41609]carbonateChEBI41609Reactome DB_ID: 97545421LTF:2xFe3+:2xCO3(2-) [phagocytic vesicle lumen]LTF:2xFe3+:2xCO3(2-)Reactome DB_ID: 12226112Reactome DB_ID: 9754540120EQUAL710EQUALReactome DB_ID: 21010512Reactome Database ID Release 759754542Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9754542ReactomeR-MMU-12224321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1222432.1Reactome Database ID Release 759754544Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9754544ReactomeR-MMU-12224911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-1222491.1Lactoferrin is secreted from many tissues to collect stray iron ions that can catalyze unwanted reactions, and to starve microorganisms of this important metal. One molecule of lactoferrin can load two ferric (Fe(3+)) ions together with two carbonate (CO3(2-)) anions (Haridas et al. 1995).15299793Pubmed1995Structure of human diferric lactoferrin refined at 2.2 A resolutionHaridas, MAnderson, BFBaker, ENActa Crystallogr D Biol Crystallogr 51:629-46inferred by electronic annotationIEAGOIEALCN2:2,5DHBA binds Fe3+LCN2:2,5DHBA binds Fe3+This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>Reactome DB_ID: 9125161Reactome DB_ID: 97813951LCN2:2,5DHBA [extracellular region]LCN2:2,5DHBAReactome DB_ID: 97813931UniProt:P11672 Lcn2Lcn2Lcn2FUNCTION Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development (PubMed:12453413). Binds iron through association with 2,5-dihydroxybenzoic acid (2,5-DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity; limits bacterial proliferation by sequestering iron bound to microbial siderophores, such as enterobactin (PubMed:15531878, PubMed:16446425). Can also bind siderophores from M.tuberculosis (By similarity).SUBUNIT Monomer. Homodimer; disulfide-linked. Heterodimer; disulfide-linked with MMP9.TISSUE SPECIFICITY Detected in lung, spleen, uterus, vagina and epididymis.INDUCTION Upon Toll-like receptor (TLRs) stimuli. By SV-40.PTM N-glycosylated.DISRUPTION PHENOTYPE Mice are normal with no visible phenotype. They however show an increased susceptibility to bacterial infections. Neutrophils show significantly less bacteriostatic activity.SIMILARITY Belongs to the calycin superfamily. Lipocalin family.UniProtP1167221EQUAL198EQUALReactome DB_ID: 522923912,5-dihydroxybenzoic acid [ChEBI:17189]2,5-dihydroxybenzoic acidChEBI17189Reactome Database ID Release 759781395Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781395ReactomeR-MMU-52292901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5229290.1Reactome DB_ID: 97813971LCN2:2,5DHBA:Fe3+ [extracellular region]LCN2:2,5DHBA:Fe3+Reactome DB_ID: 9125161Reactome DB_ID: 97813951Reactome Database ID Release 759781397Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781397ReactomeR-MMU-52292381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5229238.1Reactome Database ID Release 759781399Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9781399ReactomeR-MMU-52292731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-5229273.1Neutrophil gelatinase associated lipocalin (LCN2, NGAL) is a member of the lipocalin superfamily that is involved in iron trafficking both in and out of cells. LCN2 binds iron via an association with 2,5 dihydroxybenzoic acid (2,5DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell via interacting with different receptors, depending on cellular requirement (Goetz et al. 2002, Devireddy et al. 2010). LCN2 is a potent bacteriostatic agent in iron limiting conditions therefore it is proposed that LCN2 participates in the antibacterial iron depletion strategy of the innate immune system (Flo et al. 2004).20550936Pubmed2010A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin productionDevireddy, Laxminarayana RHart, Daniel OGoetz, David HGreen, Michael RCell 141:1006-1715531878Pubmed2004Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating ironFlo, Trude HSmith, Kelly DSato, SRodriguez, David JHolmes, Margaret AStrong, Roland KAkira, ShizuoAderem, AlanNature 432:917-2112453412Pubmed2002The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisitionGoetz, David HHolmes, Margaret ABorregaard, NielsBluhm, Martin ERaymond, Kenneth NStrong, Roland KMol. Cell 10:1033-43inferred by electronic annotationIEAGOIEAReactome Database ID Release 759819468Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9819468ReactomeR-MMU-67999901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-MMU-6799990.1Metals are necessary for all forms of life including microorganisms, evidenced by the fact that metal cations are constituents of approximately 40% of all proteins crystallized to date (Waldron KJ et al. 2009; Foster AW et al. 2014; Guengerich FP 2014, 2015). The ability of microorganisms to maintain the intracellular metal quota is essential and allows microorganisms to adapt to a variety of environments. Accordingly, the ability of the host to control metal quota at inflammation sites can influence host-pathogen interactions. The host may restrict microbial growth either by excluding essential metals from the microbes, by delivery of excess metals to cause toxicity, or by complexing metals in microorganisms (Becker KW & Skaar EP 2014).19675642Pubmed2009Metalloproteins and metal sensingWaldron, Kevin JRutherford, Julian CFord, DianneRobinson, Nigel JNature 460:823-3026055725Pubmed2015Introduction: Metals in Biology: METALS AT THE HOST-PATHOGEN INTERFACEGuengerich, FPJ. Biol. Chem. 290:18943-425160626Pubmed2014Metal preferences and metallationFoster, Andrew WOsman, DeenahRobinson, Nigel JJ. Biol. Chem. 289:28095-10325211180Pubmed2014Metal limitation and toxicity at the interface between host and pathogenBecker, Kyle WSkaar, Eric PFEMS Microbiol. Rev. 38:1235-4925160633Pubmed2014Thematic minireview series: metals in biology 2014Guengerich, FPJ. Biol. Chem. 289:28094inferred by electronic annotationIEAGOIEA