Metabolism of angiotensinogen to angiotensins (Homo sapiens)

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4, 5, 21, 22, 26...2511, 13, 28, 4319, 44152, 6, 16, 20, 22...2, 16, 241511, 23, 373, 7, 8, 12, 17...11510, 152, 16, 2410, 15, 31, 473, 7, 8, 18, 36...14, 29cytosolANPEP Dimer [plasmamembrane]ENPEP Dimer [plasmamembrane]Prorenin-ProreninReceptor [plasmamembrane]Renin:ProreninReceptor [plasmamembrane]plasma membraneH2OAGT(34-41)ANPEP DimerENPEP DimerH2OH2OENPEP [plasmamembrane]AGT(35-41)AGT(34-40)AGT(34-42)Cathepsin GACE(30-1306)CMA1H2OAGTAGT(36-41)H2OH2OaliskirenCarboxypeptidaseMMEcaptoprilCTSZANPEP [plasmamembrane]H2OACE(30-1232)AGT(34-43)enalaprilatReninH2OREN(24-406) [plasmamembrane]Renin:ProreninReceptorlisinoprilH2OH2OramiprilatACE2(18-805)ATP6AP2 [plasmamembrane]H2OATP6AP2 [plasmamembrane]H2OH2OCl-Prorenin-ProreninReceptorH2O168935, 3916


Description

Angiotensinogen, a prohormone, is synthesized and secreted mainly by the liver but also from other tissues (reviewed in Fyhrquist and Saijonmaa 2008, Cat and Touyz 2011). Renin, an aspartyl protease specific for angiotensinogen, is secreted into the bloodstream by juxtaglomerular cells of the kidney in response to a drop in blood pressure. Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Circulating renin can also bind the membrane-localized (pro)renin receptor (ATP6AP2) which increases its catalytic activity. After cleavage of angiotensinogen to angiotensin I by renin, two C-terminal amino acid residues of angiotensin I are removed by angiotensin-converting enzyme (ACE), located on the surface of endothelial cells, to yield angiotensin II (angiotensin-2, angiotensin-(1-8)), the active peptide that causes vasoconstriction, resorption of sodium and chloride, excretion of potassium, water retention, and aldosterone secretion.
More recently other, more tissue-localized pathways leading to angiotensin II and alternative derivatives of angiotensinogen have been identified (reviewed in Kramkowski et al. 2006, Kumar et al. 2007, Fyhrquist and Saijonmaa 2008, Becari et al. 2011). Chymase, cathepsin G, and cathepsin X (cathepsin Z) can each cleave angiotensin I to yield angiotensin II. Angiotensin-converting enzyme 2 (ACE2) cleaves 1 amino acid residue from angiotensin I (angiotensin-(1-10)) to yield angiotensin-(1-9), which can be cleaved by ACE to yield angiotensin-(1-7). ACE2 can also cleave angiotensin II to yield angiotensin-(1-7). Neprilysin can cleave either angiotensin-(1-9) or angiotensin I to yield angiotensin-(1-7). Angiotensin-(1-7) binds the MAS receptor (MAS1, MAS proto-oncogene) and, interestingly, produces effects opposite to those produced by angiotensin II.
Aminopeptidase A (APA, ENPEP) cleaves angiotensin II to yield angiotensin III (angiotensin-(2-8)), which is then cleaved by aminopeptidase N (APN, ANPEP) yielding angiotensin IV (angiotensin-(3-8)). Angiotensin IV binds the AT4 receptor (AT4R, IRAP, LNPEP, oxytocinase).
Inhibitors of renin (e.g. aliskiren) and ACE (e.g. lisinopril, ramipril) are currently used to treat hypertension (reviewed in Gerc et al. 2009, Verdecchia et al. 2010, Alreja and Joseph 2011).Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=2022377

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History

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CompareRevisionActionTimeUserComment
117777view13:59, 22 May 2021EweitzModified title
114755view16:24, 25 January 2021ReactomeTeamReactome version 75
113199view11:26, 2 November 2020ReactomeTeamReactome version 74
112889view13:25, 15 October 2020Fehrhartfixed screwed up complex graphics for this version
112424view15:36, 9 October 2020ReactomeTeamReactome version 73
101328view11:21, 1 November 2018ReactomeTeamreactome version 66
100866view20:54, 31 October 2018ReactomeTeamreactome version 65
100407view19:28, 31 October 2018ReactomeTeamreactome version 64
99955view16:12, 31 October 2018ReactomeTeamreactome version 63
99511view14:45, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93849view13:40, 16 August 2017ReactomeTeamreactome version 61
93407view11:22, 9 August 2017ReactomeTeamreactome version 61
87886view12:24, 25 July 2016RyanmillerOntology Term : 'peptide and protein metabolic process' added !
87885view12:23, 25 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86495view09:19, 11 July 2016ReactomeTeamreactome version 56
83131view10:04, 18 November 2015ReactomeTeamVersion54
81474view13:00, 21 August 2015ReactomeTeamVersion53
81167view14:08, 29 July 2015EgonwFixed the data source name.
76948view08:22, 17 July 2014ReactomeTeamFixed remaining interactions
76653view12:02, 16 July 2014ReactomeTeamFixed remaining interactions
75982view10:04, 11 June 2014ReactomeTeamRe-fixing comment source
75685view11:01, 10 June 2014ReactomeTeamReactome 48 Update
75041view13:55, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74685view08:45, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACE(30-1232)ProteinP12821 (Uniprot-TrEMBL)
ACE(30-1306)ProteinP12821 (Uniprot-TrEMBL)
ACE2(18-805)ProteinQ9BYF1 (Uniprot-TrEMBL)
AGT(34-40)ProteinP01019 (Uniprot-TrEMBL)
AGT(34-41)ProteinP01019 (Uniprot-TrEMBL)
AGT(34-42)ProteinP01019 (Uniprot-TrEMBL)
AGT(34-43)ProteinP01019 (Uniprot-TrEMBL)
AGT(35-41)ProteinP01019 (Uniprot-TrEMBL)
AGT(36-41)ProteinP01019 (Uniprot-TrEMBL)
AGTProteinP01019 (Uniprot-TrEMBL)
ANPEP DimerComplexREACT_148325 (Reactome)
ANPEP [plasma membrane]ProteinP15144 (Uniprot-TrEMBL)
ATP6AP2 [plasma membrane]ProteinO75787 (Uniprot-TrEMBL)
CMA1ProteinP23946 (Uniprot-TrEMBL)
CTSZProteinQ9UBR2 (Uniprot-TrEMBL) After secretion Cathepsin Z (Cathepsin X) is extracellular and associated with the plasma membrane.
CarboxypeptidaseProteinREACT_164275 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Cathepsin GProteinREACT_161260 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Cl-MetaboliteCHEBI:17996 (ChEBI)
ENPEP DimerComplexREACT_148271 (Reactome)
ENPEP [plasma membrane]ProteinQ07075 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
MMEProteinP08473 (Uniprot-TrEMBL)
Prorenin-Prorenin ReceptorComplexREACT_148518 (Reactome)
REN(24-406) [plasma membrane]ProteinP00797 (Uniprot-TrEMBL)
Renin:Prorenin ReceptorComplexREACT_148206 (Reactome)
ReninProteinREACT_160942 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
aliskirenMetaboliteCHEBI:601027 (ChEBI)
captoprilMetaboliteCHEBI:3380 (ChEBI)
enalaprilatMetaboliteCHEBI:4786 (ChEBI)
lisinoprilMetaboliteCHEBI:43755 (ChEBI)
ramiprilatMetabolite5464096 (PubChem-compound)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ACE(30-1232)mim-catalysisREACT_147705 (Reactome)
ACE(30-1306)mim-catalysisREACT_147747 (Reactome)
ACE(30-1306)mim-catalysisREACT_147855 (Reactome)
ACE2(18-805)mim-catalysisREACT_147733 (Reactome)
ACE2(18-805)mim-catalysisREACT_147889 (Reactome)
AGT(34-40)ArrowREACT_147762 (Reactome)
AGT(34-40)ArrowREACT_147787 (Reactome)
AGT(34-40)ArrowREACT_147855 (Reactome)
AGT(34-40)ArrowREACT_147889 (Reactome)
AGT(34-41)ArrowREACT_147705 (Reactome)
AGT(34-41)ArrowREACT_147744 (Reactome)
AGT(34-41)ArrowREACT_147747 (Reactome)
AGT(34-41)ArrowREACT_147760 (Reactome)
AGT(34-41)ArrowREACT_147799 (Reactome)
AGT(34-41)REACT_147872 (Reactome)
AGT(34-41)REACT_147889 (Reactome)
AGT(34-42)ArrowREACT_147733 (Reactome)
AGT(34-42)ArrowREACT_147882 (Reactome)
AGT(34-42)REACT_147762 (Reactome)
AGT(34-42)REACT_147855 (Reactome)
AGT(34-43)ArrowREACT_147720 (Reactome)
AGT(34-43)ArrowREACT_147869 (Reactome)
AGT(34-43)ArrowREACT_147891 (Reactome)
AGT(34-43)REACT_147705 (Reactome)
AGT(34-43)REACT_147733 (Reactome)
AGT(34-43)REACT_147744 (Reactome)
AGT(34-43)REACT_147747 (Reactome)
AGT(34-43)REACT_147760 (Reactome)
AGT(34-43)REACT_147787 (Reactome)
AGT(34-43)REACT_147799 (Reactome)
AGT(34-43)REACT_147882 (Reactome)
AGT(35-41)ArrowREACT_147872 (Reactome)
AGT(35-41)REACT_147767 (Reactome)
AGT(36-41)ArrowREACT_147767 (Reactome)
AGTREACT_147720 (Reactome)
AGTREACT_147869 (Reactome)
AGTREACT_147891 (Reactome)
ANPEP Dimermim-catalysisREACT_147767 (Reactome)
CMA1mim-catalysisREACT_147760 (Reactome)
CTSZmim-catalysisREACT_147799 (Reactome)
Carboxypeptidasemim-catalysisREACT_147882 (Reactome)
Cathepsin Gmim-catalysisREACT_147744 (Reactome)
Cl-ArrowREACT_147705 (Reactome)
Cl-ArrowREACT_147747 (Reactome)
ENPEP Dimermim-catalysisREACT_147872 (Reactome)
H2OREACT_147705 (Reactome)
H2OREACT_147720 (Reactome)
H2OREACT_147733 (Reactome)
H2OREACT_147744 (Reactome)
H2OREACT_147747 (Reactome)
H2OREACT_147760 (Reactome)
H2OREACT_147762 (Reactome)
H2OREACT_147767 (Reactome)
H2OREACT_147787 (Reactome)
H2OREACT_147799 (Reactome)
H2OREACT_147855 (Reactome)
H2OREACT_147869 (Reactome)
H2OREACT_147872 (Reactome)
H2OREACT_147882 (Reactome)
H2OREACT_147889 (Reactome)
H2OREACT_147891 (Reactome)
MMEmim-catalysisREACT_147762 (Reactome)
MMEmim-catalysisREACT_147787 (Reactome)
Prorenin-Prorenin Receptormim-catalysisREACT_147720 (Reactome)
REACT_147705 (Reactome) Secreted angiotensin-converting enzyme (ACE) cleaves 2 amino acid residues from the C-terminus of angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Wei et al. 1991). This reaction is inhibited by drugs used to treat hypertension (angiotensin converting enzyme inhibitors, ACEI) including captopril (Gronhagen-Riska and Fyhrquist 1980, Stewart et al. 1981, Ehlers et al. 1986, Hayakari et al. 1989, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), enalaprilat (metablized from the prodrug enalapril, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), lisinopril ( Ehlers et al. 1991, Natesh et al. 2003), and ramiprilat (metabolized from the prodrug ramipril, Baudin and Beneteau-Burnat 1999). ACE is secreted ("shed") from membranes of endothelial cells by cleavage in the C-terminal region that removes the membrane anchor.
REACT_147720 (Reactome) The binding of prorenin to the (pro)renin receptor activates the protease activity of prorenin, which can then hydrolyze angiotensinogen to yield angiotensin-(1-10) (angiotensin I) (Nguyen et al. 2002). Prorenin is inactive when not bound to the (pro)renin receptor. Aliskiren, a drug used clinically to treat hypertension, inhibits the cleavage of angiotensinogen by renin (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009).
REACT_147733 (Reactome) 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).
REACT_147744 (Reactome) Cathepsin G hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Reilly et al. 1982, Owen and Campbell 1998, Raymond et al. 2010). Cathepsin bound to the plasma membrane of neutrophils has a higher activity than does soluble cathepsin G (Owen and Campbell 1998).
REACT_147747 (Reactome) Angiotensin-converting enzyme (ACE) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Ehlers and Kirsch 1988). ACE is found at the plasma membrane of endothelial cells. This reaction is inhibited by drugs used to treat hypertension (angiotensin converting enzyme inhibitors, ACEI) including captopril (Gronhagen-Riska and Fyhrquist 1980, Stewart et al. 1981, Ehlers et al. 1986, Hayakari et al. 1989, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), enalaprilat (metablized from the prodrug enalapril, Wei et al. 1991, Baudin and Beneteau-Burnat 1999), lisinopril ( Ehlers et al. 1991, Natesh et al. 2003), and ramiprilat (metabolized from the prodrug ramipril, Baudin and Beneteau-Burnat 1999).
REACT_147760 (Reactome) Chymase hydrolyzes angiotensin-(1-10) (angiotensin) to yield angiotensin-(1-8) (angiotensin II) at a higher rate than does angiotensin-converting enzyme (Reilly et al. 1982, Urata et al. 1990, Caughey et al. 2000, Richard et al. 2001).
REACT_147762 (Reactome) Neprilysin hydrolyzes angiotensin-(1-9) to yield angiotensin-(1-7) (Rice et al. 2004). The hydrolysis of angiotensin-(1-9) catalyzed by neprilysin is more efficient than that catalyzed by angiotensin-converting enzyme (ACE) (Rice et al. 2004).
REACT_147767 (Reactome) Aminopeptidase N (APN, ANPEP, aminopeptidase M, alanyl aminopeptidase) hydrolyzes angiotensin-(2-8) (angiotensin III) to yield angiotensin-(3-8) (angiotensin IV) (see the positive control reactions in Diaz-Perales et al. 2005). Aminopeptidase O (AOPEP) also hydrolyzes angiotensin-(2-8) to angiotensin-(3-8) in vitro (Diaz-Perales et al. 2005) but AOPEP is located in the nucleolus in vivo (Axton et al. 2008) and angiotensin-(2-8) has not been observed in the nucleus.
REACT_147787 (Reactome) Neprilysin hydrolyzes angiotensin-(1-10) (angiotensin I) directly to angiotensin-(1-7) (Rice et al. 2004).
REACT_147799 (Reactome) Cathepsin Z (cathepsin X) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Nagler et al. 2010).
REACT_147855 (Reactome) Angiotensin-converting enzyme (ACE) hydrolyzes angiotensin-(1-9) to yield angiotensin-(1-7) (Rice et al. 2004).
REACT_147869 (Reactome) Renin in the bloodstream hydrolyzes angiotensinogen to yield angiotensin-(1-10) (angiotensin I). Renin is produced in the juxtaglomerular cells of the kidney in response to reduced blood pressure. Aliskiren, a drug used clinically to treat hypertension, inhibits this reaction (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009).
REACT_147872 (Reactome) Aminopeptidase A (APA, ENPEP) hydrolyzes the N-terminal amino acid of angiotensin-(1-8) (angiotensin II) to yield angiotensin-(2-8) (angiotensin III) (Goto et al. 2006). The catalysis is more specific and efficient in the presence of calcium ions (Goto et al. 2006).
REACT_147882 (Reactome) Mast cell carboxypeptidase (CPA3) hydrolyzes a single amino acid residue from the C-terminus of angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-9).
REACT_147889 (Reactome) Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin-(1-8) (angiotensin II) to yield angiotensin-(1-7) (Vickers et al. 2002, Rice et al. 2004). The activity of ACE2 on angiotensin-(1-8) is 400-fold higher than on angiotensin-(1-10) (Vickers et al. 2002).
REACT_147891 (Reactome) Renin bound to the (pro)renin receptor (ATP6AP2) hydrolyzes angiotensinogen to yield angiotensin-(1-10) (angiotensin I) (Nguyen et al. 2002). Binding to the (pro)renin receptor increases the catalytic efficiency of renin 4-fold (Nguyen et al. 2002). Aliskiren, a drug used clinically to treat hypertension, inhibits cleavage of angiotensinogen by renin (Gossas et al. 2011, Wood et al. 2003, reviewed in Gerc et al. 2009).
Renin:Prorenin ReceptorArrowREACT_147891 (Reactome)
Renin:Prorenin Receptormim-catalysisREACT_147891 (Reactome)
Reninmim-catalysisREACT_147869 (Reactome)
aliskirenTBarREACT_147720 (Reactome)
aliskirenTBarREACT_147869 (Reactome)
aliskirenTBarREACT_147891 (Reactome)
captoprilTBarREACT_147705 (Reactome)
captoprilTBarREACT_147747 (Reactome)
enalaprilatTBarREACT_147705 (Reactome)
enalaprilatTBarREACT_147747 (Reactome)
lisinoprilTBarREACT_147705 (Reactome)
lisinoprilTBarREACT_147747 (Reactome)
ramiprilatTBarREACT_147705 (Reactome)
ramiprilatTBarREACT_147747 (Reactome)
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