BioPAX pathway converted from "ACE2 hydrolyzes Angiotensin-(1-10) to Angiotensin-(1-9)" in the Reactome database. LEFT-TO-RIGHT 3.4.17.22 3.4.17.4 3.4.17.10 3.4.17.21 3.4.17.3 3.4.17.6 3.4.17.2 3.4.17.1 3.4.17.17 ACE2 hydrolyzes Angiotensin-(1-10) to Angiotensin-(1-9) ACE2 Hydrolyzes Angiotensin I to Yield Angiotensin-(1-9) Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-9) (Donoghue et al. 2000, Tipnis et al. 2000, Vickers et al. 2002, Rice t al. 2004). The activity of ACE2 on angiotensin I is weak (Rice et al. 2004), being 400-fold lower than the activity of ACE2 on angiotensin II (Vickers et al. 2002). Authored: May, B, 2011-11-19 Reviewed: Joseph, J, 2012-08-06 Edited: May, B, 2011-11-19 AGT AGT(34-43) Angiotensin-(1-10) Angiotensin I Angiotensin-1 ANGT_HUMAN ANG1-10 Reactome DB_ID: 2022346 extracellular region GENE ONTOLOGY GO:0005576 UniProt:P01019 AGT AGT SERPINA8 FUNCTION Essential component of the renin-angiotensin system (RAS), a potent regulator of blood pressure, body fluid and electrolyte homeostasis.SUBUNIT During pregnancy, exists as a disulfide-linked 2:2 heterotetramer with the proform of PRG2 and as a complex (probably a 2:2:2 heterohexamer) with pro-PRG2 and C3dg.TISSUE SPECIFICITY Expressed by the liver and secreted in plasma.PTM Beta-decarboxylation of Asp-34 in angiotensin-2, by mononuclear leukocytes produces alanine (PubMed:17138938). The resulting peptide form, angiotensin-A, has the same affinity for the AT1 receptor as angiotensin-2, but a higher affinity for the AT2 receptor (PubMed:17138938).PTM In response to low blood pressure, the enzyme renin/REN cleaves angiotensinogen to produce angiotensin-1 (PubMed:12045255). Angiotensin-1 is a substrate of ACE (angiotensin converting enzyme) that removes a dipeptide to yield the physiologically active peptide angiotensin-2 (PubMed:4322742, PubMed:10969042). Angiotensin-1 and angiotensin-2 can be further processed to generate angiotensin-3, angiotensin-4 (PubMed:10969042, PubMed:11815627). Angiotensin 1-9 is cleaved from angiotensin-1 by ACE2 and can be further processed by ACE to produce angiotensin 1-7, angiotensin 1-5 and angiotensin 1-4 (PubMed:10969042, PubMed:11815627). Angiotensin 1-7 has also been proposed to be cleaved from angiotensin-2 by ACE2 or from angiotensin-1 by MME (neprilysin) (PubMed:15283675).PTM The disulfide bond is labile. Angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized disulfide-bonded form, which preferentially interacts with receptor-bound renin.SIMILARITY Belongs to the serpin family.CAUTION It is uncertain whether Met-1 or Met-10 is the initiator. Homo sapiens NCBI Taxonomy 9606 UniProt P01019 34 EQUAL 43 EQUAL Reactome Database ID Release 82 2022346 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=2022346 Reactome R-HSA-2022346 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-HSA-2022346.1 Reactome http://www.reactome.org H2O water Reactome DB_ID: 109276 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 82 109276 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=109276 Reactome R-ALL-109276 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-109276.4 COMPOUND C00001 additional information MI MI:0361 AGT AGT(34-42) Angiotensin-(1-9) Ang-(1-9) ANGT_HUMAN Reactome DB_ID: 2022348 34 EQUAL 42 EQUAL Reactome Database ID Release 82 2022348 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=2022348 Reactome R-HSA-2022348 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-HSA-2022348.1 ACTIVATION ACE2 ACE2(18-805) Angiotensin-converting enzyme 2 ACE2_HUMAN Reactome DB_ID: 2022344 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:Q9BYF1 ACE2 ACE2 UNQ868/PRO1885 FUNCTION Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis (PubMed:27217402). Converts angiotensin I to angiotensin 1-9, a nine-amino acid peptide with anti-hypertrophic effects in cardiomyocytes, and angiotensin II to angiotensin 1-7, which then acts as a beneficial vasodilator and anti-proliferation agent, counterbalancing the actions of the vasoconstrictor angiotensin II (PubMed:10969042, PubMed:10924499, PubMed:11815627, PubMed:19021774, PubMed:14504186). Also removes the C-terminal residue from three other vasoactive peptides, neurotensin, kinetensin, and des-Arg bradykinin, but is not active on bradykinin (PubMed:10969042, PubMed:11815627). Also cleaves other biological peptides, such as apelins (apelin-13, [Pyr1]apelin-13, apelin-17, apelin-36), casomorphins (beta-casomorphin-7, neocasomorphin) and dynorphin A with high efficiency (PubMed:11815627, PubMed:27217402, PubMed:28293165). In addition, ACE2 C-terminus is homologous to collectrin and is responsible for the trafficking of the neutral amino acid transporter SL6A19 to the plasma membrane of gut epithelial cells via direct interaction, regulating its expression on the cell surface and its catalytic activity (PubMed:18424768, PubMed:19185582).FUNCTION (Microbial infection) Acts as a receptor for human coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus NL63/HCoV-NL63.ACTIVITY REGULATION Regulated by chloride and fluoride, but not bromide (PubMed:11815627). Chloride increases angiotensin I and decreases angiotensin II cleavage (PubMed:19021774). Inhibited by MLN-4760, cFP_Leu, and EDTA (PubMed:15231706, PubMed:10924499), but not by the ACE inhibitors lisinopril, captopril and enalaprilat (PubMed:10969042, PubMed:10924499). Highly potent and selective in vitro ACE2 inhibitors were identified (PubMed:12358520).SUBUNIT Homodimer (PubMed:32132184). Interacts with the catalytically active form of TMPRSS2 (PubMed:21068237). Interacts with SLC6A19; this interaction is essential for expression and function of SLC6A19 in intestine (By similarity). Interacts with ITGA5:ITGB1 (PubMed:15276642, PubMed:33102950). Probably interacts (via endocytic sorting signal motif) with AP2M1; the interaction is inhibited by phosphorylation of Tyr-781 (PubMed:33436498). Interacts (via PDZ-binding motif) with SLC9A3R1 (via PDZ domains); the interaction may enhance ACE2 membrane residence (PubMed:34189428).SUBUNIT (Microbial infection) Interacts with SARS coronavirus/SARS-CoV spike protein.SUBUNIT (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein.SUBUNIT (Microbial infection) Interacts with human coronavirus NL63 spike protein.SUBUNIT (Microbial infection) Interacts with human coronavirus NL63/HCoV-NL63 spike glycoprotein.TISSUE SPECIFICITY Expressed in endothelial cells from small and large arteries, and in arterial smooth muscle cells (at protein level) (PubMed:15141377). Expressed in enterocytes of the small intestine, Leydig cells and Sertoli cells (at protein level) (PubMed:15141377). Expressed in the renal proximal tubule and the small intestine (at protein level) (PubMed:18424768). Expressed in heart, kidney, testis, and gastrointestinal system (at protein level) (PubMed:10969042, PubMed:10924499, PubMed:15231706, PubMed:12459472, PubMed:15671045, PubMed:32715618, PubMed:32170560). In lung, expressed at low levels in some alveolar type 2 cells, the expression seems to be individual-specific (at protein level) (PubMed:32425701, PubMed:15141377, PubMed:32715618, PubMed:32170560, PubMed:33432184). Expressed in nasal epithelial cells (at protein level) (PubMed:33432184, PubMed:32333915). Coexpressed with TMPRSS2 within some lung alveolar type 2 cells, ileal absorptive enterocytes, intestinal epithelial cells, cornea, gallbladder and nasal goblet secretory cells (PubMed:32413319, PubMed:32327758, PubMed:32358202). Coexpressed with TMPRSS4 within mature enterocytes (PubMed:32404436).INDUCTION Up-regulated in failing heart (PubMed:14504186, PubMed:15151696, PubMed:15671045). Expression is induced by IFNA and IFNG (PubMed:32413319, PubMed:32425701). Exposure to cigarette smoke increases expression in lungs (PubMed:32425701). Expression is decreased in nasal and bronchial epithelium of individuals with allergy after allergen challenge (PubMed:32333915). IL13 stimulation decreases expression in nasal and bronchial epithelium (PubMed:32333915).INDUCTION (Microbial infection) In airway epithelial cells, expression is increased upon influenza A virus infection (PubMed:32413319).DOMAIN The extracellular region of the ACE2 enzyme is composed of two domains. The first is a zinc metallopeptidase domain (residues 19-611). The second domain is located at the C-terminus (residues 612-740) and is 48% identical to human collectrin.DOMAIN The cytoplasmic tail contains several linear motifs such as LIR, PDZ-binding, PTB and endocytic sorting signal motifs that would allow interaction with proteins that mediate endocytic trafficking and autophagy.PTM N-glycosylation on Asn-90 may limit SARS infectivity.PTM Proteolytic cleavage by ADAM17 generates a secreted form (PubMed:15983030, PubMed:33713620). Also cleaved by serine proteases: TMPRSS2, TMPRSS11D and HPN/TMPRSS1.PTM Phosphorylated. Phosphorylation at Tyr-781 probably inhibits interaction with AP2M1 and enables interactions with proteins containing SH2 domains.BIOTECHNOLOGY An engeneered stable, dimeric and secreted receptor with combined mutations that increase the affinity for human coronavirus SARS-CoV-2 spike protein shows potent SARS-CoV and SARS-CoV-2 neutralization in vitro.SIMILARITY Belongs to the peptidase M2 family. UniProt Q9BYF1 18 EQUAL 805 EQUAL Reactome Database ID Release 82 2022344 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=2022344 Reactome R-HSA-2022344 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-HSA-2022344.1 GENE ONTOLOGY GO:0004181 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 2022376 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=2022376 Reactome Database ID Release 82 2022378 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=2022378 Reactome R-HSA-2022378 2 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-HSA-2022378.2 15283675 Pubmed 2004 Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism Rice, GI Thomas, DA Grant, PJ Turner, AJ Hooper, NM Biochem J 383:45-51 10924499 Pubmed 2000 A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase Tipnis, SR Hooper, NM Hyde, R Karran, E Christie, G Turner, AJ J Biol Chem 275:33238-43 10969042 Pubmed 2000 A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9 Donoghue, M Hsieh, F Baronas, E Godbout, K Gosselin, M Stagliano, N Donovan, M Woolf, B Robison, K Jeyaseelan, R Breitbart, RE Acton, S Circ Res 87:E1-9 11815627 Pubmed 2002 Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase Vickers, C Hales, P Kaushik, V Dick, L Gavin, J Tang, J Godbout, K Parsons, T Baronas, E Hsieh, F Acton, S Patane, M Nichols, A Tummino, P J Biol Chem 277:14838-43 GENE ONTOLOGY GO:0002003 gene ontology term for cellular process MI MI:0359