BioPAX pathway converted from "Metal sequestration by antimicrobial proteins" in the Reactome database. Metal sequestration by antimicrobial proteins 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> LEFT-TO-RIGHT 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> Na+ sodium ion sodium(1+) Sodium Reactome DB_ID: 74113 extracellular region GENE ONTOLOGY GO:0005576 sodium(1+) [ChEBI:29101] sodium(1+) ChEBI CHEBI:29101 Reactome Database ID Release 78 74113 Database 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=74113 Reactome R-ALL-74113 3 Reactome 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-ALL-74113.3 Reactome http://www.reactome.org COMPOUND C01330 additional information MI MI:0361 2 Mn2+ Manganese manganese(2+) Mn(II) Reactome DB_ID: 266099 manganese(2+) [ChEBI:29035] manganese(2+) Mn(2+) MANGANESE (II) ION manganese, ion (Mn2+) manganese(II) manganous ion ChEBI CHEBI:29035 Reactome Database ID Release 78 266099 Database 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=266099 Reactome R-ALL-266099 3 Reactome 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-ALL-266099.3 COMPOUND C00034 2 S100A8:S100A9:Ca2+ Reactome DB_ID: 9835814 S100A8:S100A9 Reactome DB_ID: 9823491 S100a8 S100A8 P27005 Reactome DB_ID: 9823485 UniProt:P27005 S100a8 Mus musculus NCBI Taxonomy 10090 UniProt P27005 1 EQUAL 93 EQUAL Reactome Database ID Release 78 9823485 Database 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=9823485 Reactome R-MMU-5432846 1 Reactome 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-5432846.1 1 S100a9 S100A9 P31725 Reactome DB_ID: 9823489 UniProt:P31725 S100a9 UniProt P31725 2 EQUAL 114 EQUAL Reactome Database ID Release 78 9823489 Database 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=9823489 Reactome R-MMU-5432857 1 Reactome 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-5432857.1 1 Reactome Database ID Release 78 9823491 Database 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=9823491 Reactome R-MMU-5432834 1 Reactome 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-5432834.1 2 Ca2+ Calcium calcium(2+) Reactome DB_ID: 74112 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 78 74112 Database 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=74112 Reactome R-ALL-74112 4 Reactome 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-ALL-74112.4 COMPOUND C00076 4 Reactome Database ID Release 78 9835814 Database 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=9835814 Reactome R-MMU-8944198 1 Reactome 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-8944198.1 S100A8:S100A9:Ca2+:Mn2+:Na+ Reactome DB_ID: 9835820 2 2 1 Reactome Database ID Release 78 9835820 Database 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=9835820 Reactome R-MMU-6798411 1 Reactome 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-6798411.1 Reactome Database ID Release 78 9835822 Database 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=9835822 Reactome R-MMU-6798528 1 Reactome 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-6798528.1 S100A8 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. 22127564 Pubmed 2012 Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4 Schelbergen, Rik F P Blom, Arjen B van den Bosch, Martijn H J Slöetjes, Annet Abdollahi-Roodsaz, Shahla Schreurs, B Wim Mort, John S Vogl, Thomas Roth, Johannes van den Berg, Wim B van Lent, Peter L E M Arthritis Rheum. 64:1477-87 11991838 Pubmed 2002 S100 proteins: structure, functions and pathology Heizmann, CW Fritz, Günter Schäfer, Beat W Front. Biosci. 7:d1356-68 8445331 Pubmed 1993 MRP-8 and MRP-14, two abundant Ca(2+)-binding proteins of neutrophils and monocytes Hessian, P A Edgeworth, J Hogg, N J. Leukoc. Biol. 53:197-204 15191538 Pubmed 2004 S100 proteins in the epidermis Eckert, Richard L Broome, Ann-Marie Ruse, Monica Robinson, Nancy Ryan, D Lee, Kathleen J. Invest. Dermatol. 123:23-33 7552751 Pubmed 1995 The structure of calcyclin reveals a novel homodimeric fold for S100 Ca(2+)-binding proteins Potts, B C Smith, J Akke, M Macke, T J Okazaki, K Hidaka, H Case, D A Chazin, W J Nat. Struct. Biol. 2:790-6 17767165 Pubmed 2007 Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock Vogl, Thomas Tenbrock, Klaus Ludwig, Stephan Leukert, Nadja Ehrhardt, Christina van Zoelen, Marieke A D Nacken, Wolfgang Foell, Dirk van der Poll, Tom Sorg, Clemens Roth, Johannes Nat. Med. 13:1042-9 16216873 Pubmed 2005 S100A8 and S100A9 in human arterial wall. Implications for atherogenesis McCormick, Michelle M Rahimi, Farid Bobryshev, Yuri V Gaus, Katharina Zreiqat, Hala Cai, Hong Lord, Reginald S A Geczy, Carolyn L J. Biol. Chem. 280:41521-9 15598812 Pubmed 2005 Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells Viemann, Dorothee Strey, Anke Janning, Annette Jurk, Kerstin Klimmek, Kerstin Vogl, Thomas Hirono, Keiichi Ichida, Fukiko Foell, Dirk Kehrel, Beate Gerke, Volker Sorg, Clemens Roth, Johannes Blood 105:2955-62 17553524 Pubmed 2007 The 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 proteins Korndörfer, Ingo P Brueckner, Florian Skerra, Arne J. Mol. Biol. 370:887-98 22834835 Pubmed 2013 Functions of S100 proteins Donato, R Cannon, B R Sorci, G Riuzzi, F Hsu, K Weber, D J Geczy, C L Curr. Mol. Med. 13:24-57 10026247 Pubmed 1999 Zinc-binding site of an S100 protein revealed. Two crystal structures of Ca2+-bound human psoriasin (S100A7) in the Zn2+-loaded and Zn2+-free states Brodersen, D E Nyborg, J Kjeldgaard, M Biochemistry 38:1695-704 23082970 Pubmed 2012 Calcium ion gradients modulate the zinc affinity and antibacterial activity of human calprotectin Brophy, Megan Brunjes Hayden, Joshua A Nolan, Elizabeth M J. Am. Chem. Soc. 134:18089-100 23276281 Pubmed 2013 High-affinity manganese coordination by human calprotectin is calcium-dependent and requires the histidine-rich site formed at the dimer interface Hayden, Joshua A Brophy, Megan Brunjes Cunden, Lisa S Nolan, Elizabeth M J. Am. Chem. Soc. 135:775-87 15699168 Pubmed 2005 Regulation of S100A8 by glucocorticoids Hsu, Kenneth Passey, Robert J Endoh, Yasumi Rahimi, Farid Youssef, Peter Yen, Tina Geczy, Carolyn L J. Immunol. 174:2318-26 26055713 Pubmed 2015 Nutritional Immunity: S100 Proteins at the Host-Pathogen Interface Zackular, Joseph P Chazin, Walter J Skaar, Eric P J. Biol. Chem. 290:18991-8 23431180 Pubmed 2013 Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens Damo, Steven M Kehl-Fie, Thomas E Sugitani, Norie Holt, Marilyn E Rathi, Subodh Murphy, Wesley J Zhang, Yaofang Betz, Christine Hench, Laura Fritz, Günter Skaar, Eric P Chazin, Walter J Proc. Natl. Acad. Sci. U.S.A. 110:3841-6 21843872 Pubmed 2011 Nutrient metal sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil killing of Staphylococcus aureus Kehl-Fie, Thomas E Chitayat, Seth Hood, M Indriati Damo, Steven Restrepo, Nicole Garcia, Carlos Munro, Kim A Chazin, Walter J Skaar, Eric P Cell Host Microbe 10:158-64 26302479 Pubmed 2015 Human calprotectin is an iron-sequestering host-defense protein Nakashige, Toshiki G Zhang, Bo Krebs, Carsten Nolan, Elizabeth M Nat. Chem. Biol. 11:765-71 16682612 Pubmed 2006 Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events Healy, Aileen M Pickard, Michael D Pradhan, Aruna D Wang, Yunmei Chen, Zhiping Croce, Kevin Sakuma, Masashi Shi, Can Zago, Alexandre C Garasic, Joseph Damokosh, Andrew I Dowie, Tracy L Poisson, Louis Lillie, James Libby, Peter Ridker, Paul M Simon, Daniel I Circulation 113:2278-84 19386136 Pubmed 2009 Both Ca2+ and Zn2+ are essential for S100A12 protein oligomerization and function Moroz, Olga V Burkitt, Will Wittkowski, Helmut He, Wei Ianoul, Anatoli Novitskaya, Vera Xie, Jingjing Polyakova, Oxana Lednev, Igor K Shekhtman, Alexander Derrick, Peter J Bjoerk, Per Foell, Dirk Bronstein, Igor B BMC Biochem. 10:11 25597447 Pubmed 2015 Manganese binding properties of human calprotectin under conditions of high and low calcium: X-ray crystallographic and advanced electron paramagnetic resonance spectroscopic analysis Gagnon, Derek M Brophy, Megan Brunjes Bowman, Sarah E J Stich, Troy A Drennan, Catherine L Britt, R David Nolan, Elizabeth M J. Am. Chem. Soc. 137:3004-16 14555857 Pubmed 2003 Interleukin-10 influences the expression of MRP8 and MRP14 in human dendritic cells Kumar, Anita Steinkasserer, Alexander Berchtold, Susanne Int. Arch. Allergy Immunol. 132:40-7 24245608 Pubmed 2013 Contributions of the S100A9 C-terminal tail to high-affinity Mn(II) chelation by the host-defense protein human calprotectin Brophy, Megan Brunjes Nakashige, Toshiki G Gaillard, Aleth Nolan, Elizabeth M J. Am. Chem. Soc. 135:17804-17 16690079 Pubmed 2006 Calcium-dependent tetramer formation of S100A8 and S100A9 is essential for biological activity Leukert, Nadja Vogl, Thomas Strupat, Kerstin Reichelt, Rudolf Sorg, Clemens Roth, Johannes J. Mol. Biol. 359:961-72 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT 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> Zn2+ Zn++ zinc(2+) Zinc ion Zn(II) Reactome DB_ID: 158417 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 78 158417 Database 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=158417 Reactome R-ALL-158417 3 Reactome 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-ALL-158417.3 COMPOUND C00038 4 S100A8:S100A9:Ca2+:Zn2+ Reactome DB_ID: 9835816 4 2 4 Reactome Database ID Release 78 9835816 Database 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=9835816 Reactome R-MMU-8944189 1 Reactome 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-8944189.1 Reactome Database ID Release 78 9835818 Database 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=9835818 Reactome R-MMU-6798474 1 Reactome 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-6798474.1 Two 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. LEFT-TO-RIGHT Lactoferrin scavenges iron ions 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> Fe3+ iron (ferric) iron(3+) Reactome DB_ID: 1222611 phagocytic vesicle lumen GENE ONTOLOGY GO:0097013 iron(3+) [ChEBI:29034] iron(3+) ferric iron iron, ion (Fe(3+)) Fe(3+) Fe(III) Fe3+ FE (III) ION Ferric ion ChEBI CHEBI:29034 Reactome Database ID Release 78 1222611 Database 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=1222611 Reactome R-ALL-1222611 3 Reactome 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-ALL-1222611.3 2 CO3(2-) Carbonate (2-) carbonate Reactome DB_ID: 2101051 carbonate [ChEBI:41609] carbonate ChEBI CHEBI:41609 Reactome Database ID Release 78 2101051 Database 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=2101051 Reactome R-ALL-2101051 3 Reactome 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-ALL-2101051.3 2 Ltf LTF P08071 Reactome DB_ID: 9795449 UniProt:P08071 Ltf UniProt P08071 20 EQUAL 710 EQUAL Reactome Database ID Release 78 9795449 Database 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=9795449 Reactome R-MMU-1222567 1 Reactome 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-1222567.1 LTF:2xFe3+:2xCO3(2-) Reactome DB_ID: 9795451 2 2 1 Reactome Database ID Release 78 9795451 Database 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=9795451 Reactome R-MMU-1222432 1 Reactome 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-1222432.1 Reactome Database ID Release 78 9795453 Database 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=9795453 Reactome R-MMU-1222491 1 Reactome 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-1222491.1 Lactoferrin 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). 15299793 Pubmed 1995 Structure of human diferric lactoferrin refined at 2.2 A resolution Haridas, M Anderson, BF Baker, EN Acta Crystallogr D Biol Crystallogr 51:629-46 LEFT-TO-RIGHT 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> Fe3+ iron (3+) iron(3+) ferric iron Reactome DB_ID: 912516 Reactome Database ID Release 78 912516 Database 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=912516 Reactome R-ALL-912516 5 Reactome 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-ALL-912516.5 LCN2:2,5DHBA Reactome DB_ID: 9821782 2.5DHBA 2,5-dihydroxybenzoate 2,5-dihydroxybenzoic acid Reactome DB_ID: 5229239 2,5-dihydroxybenzoic acid [ChEBI:17189] 2,5-dihydroxybenzoic acid ChEBI CHEBI:17189 Reactome Database ID Release 78 5229239 Database 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=5229239 Reactome R-ALL-5229239 3 Reactome 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-ALL-5229239.3 1 Lcn2 LCN2 P11672 Reactome DB_ID: 9821780 UniProt:P11672 Lcn2 Lcn2 FUNCTION Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development (PubMed:12453413). Binds iron through association with 2,3-dihydroxybenzoic acid (2,3-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. UniProt P11672 21 EQUAL 198 EQUAL Reactome Database ID Release 78 9821780 Database 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=9821780 Reactome R-MMU-5215934 1 Reactome 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-5215934.1 1 Reactome Database ID Release 78 9821782 Database 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=9821782 Reactome R-MMU-5229290 1 Reactome 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-5229290.1 LCN2:2,5DHBA:Fe3+ Reactome DB_ID: 9821784 1 1 Reactome Database ID Release 78 9821784 Database 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=9821784 Reactome R-MMU-5229238 1 Reactome 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-5229238.1 Reactome Database ID Release 78 9821786 Database 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=9821786 Reactome R-MMU-5229273 1 Reactome 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-5229273.1 Neutrophil 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). 15531878 Pubmed 2004 Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron Flo, Trude H Smith, Kelly D Sato, S Rodriguez, David J Holmes, Margaret A Strong, Roland K Akira, Shizuo Aderem, Alan Nature 432:917-21 20550936 Pubmed 2010 A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production Devireddy, Laxminarayana R Hart, Daniel O Goetz, David H Green, Michael R Cell 141:1006-17 12453412 Pubmed 2002 The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition Goetz, David H Holmes, Margaret A Borregaard, Niels Bluhm, Martin E Raymond, Kenneth N Strong, Roland K Mol. Cell 10:1033-43 Reactome Database ID Release 78 9862094 Database 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=9862094 Reactome R-MMU-6799990 1 Reactome 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-6799990.1 Metals 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). 25211180 Pubmed 2014 Metal limitation and toxicity at the interface between host and pathogen Becker, Kyle W Skaar, Eric P FEMS Microbiol. Rev. 38:1235-49 25160626 Pubmed 2014 Metal preferences and metallation Foster, Andrew W Osman, Deenah Robinson, Nigel J J. Biol. Chem. 289:28095-103 26055725 Pubmed 2015 Introduction: Metals in Biology: METALS AT THE HOST-PATHOGEN INTERFACE Guengerich, FP J. Biol. Chem. 290:18943-4 19675642 Pubmed 2009 Metalloproteins and metal sensing Waldron, Kevin J Rutherford, Julian C Ford, Dianne Robinson, Nigel J Nature 460:823-30 25160633 Pubmed 2014 Thematic minireview series: metals in biology 2014 Guengerich, FP J. Biol. Chem. 289:28094