Metabolism of angiotensinogen to angiotensins (Homo sapiens)

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2-4, 6, 7, 12...5, 10, 11, 29, 30, 32...451, 9, 51224522, 2716, 37, 42, 4314, 5415, 17, 4345, 49201, 2, 9, 19, 21...3531, 393418, 33, 535, 10, 11, 32, 36...45, 48-501, 9, 5145endoplasmic reticulum membranecytosolplasma membraneGZMH ACEIsAOPEP:Zn2+ANPEP Prorenin-ProreninReceptorCPB2 H2OATP6AP2 ACEIs:ACE(30-1232)hydrolysed ACEIsCES1 trimerH2OAlcoholCMA1ACE2(18-805)AGT(34-40)H2OANPEP DimerCathepsin GH2OREN(24-406) H2OH2Ohydrolysed ACEIsH2OACE(30-1232)MMEH2OACEI pro-drugsATP6AP2 aliskirenReninREN AGT(36-41)ACE(30-1306)CTSZCES1 CPA3 CTSD(65-412) AGT(34-43)H2OH2ORenin:ProreninReceptorH2OCPB1 ENPEP L-ArgENPEP DimerAGT(34-41)CTSG H2OAGT(35-41)H2OACE(30-1232) AGTCl-AGT(36-41)AGT(35-41)AOPEP CTSD(65-412) AGT(34-42)H2OH2OREN Zn2+ Carboxypeptidase514440448, 28465114


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). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 2022377
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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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

View all...
NameTypeDatabase referenceComment
ACE(30-1232) ProteinP12821 (Uniprot-TrEMBL)
ACE(30-1232)ProteinP12821 (Uniprot-TrEMBL)
ACE(30-1306)ProteinP12821 (Uniprot-TrEMBL)
ACE2(18-805)ProteinQ9BYF1 (Uniprot-TrEMBL)
ACEI pro-drugsComplexR-ALL-9619052 (Reactome)
ACEIs:ACE(30-1232)ComplexR-HSA-9614931 (Reactome)
ACEIsComplexR-ALL-9614913 (Reactome)
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 DimerComplexR-HSA-2022361 (Reactome)
ANPEP ProteinP15144 (Uniprot-TrEMBL)
AOPEP ProteinQ8N6M6 (Uniprot-TrEMBL)
AOPEP:Zn2+ComplexR-HSA-8852197 (Reactome)
ATP6AP2 ProteinO75787 (Uniprot-TrEMBL)
AlcoholMetaboliteCHEBI:30879 (ChEBI)
CES1 ProteinP23141 (Uniprot-TrEMBL)
CES1 trimerComplexR-HSA-5693667 (Reactome)
CMA1ProteinP23946 (Uniprot-TrEMBL)
CPA3 ProteinP15088 (Uniprot-TrEMBL)
CPB1 ProteinP15086 (Uniprot-TrEMBL)
CPB2 ProteinQ96IY4 (Uniprot-TrEMBL)
CTSD(65-412) ProteinP07339 (Uniprot-TrEMBL)
CTSG ProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
CTSZProteinQ9UBR2 (Uniprot-TrEMBL) After secretion Cathepsin Z (Cathepsin X) is extracellular and associated with the plasma membrane.
CarboxypeptidaseComplexR-HSA-3229246 (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 GComplexR-HSA-2990877 (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 DimerComplexR-HSA-2022357 (Reactome)
ENPEP ProteinQ07075 (Uniprot-TrEMBL)
GZMH ProteinP20718 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
L-ArgMetaboliteCHEBI:32682 (ChEBI)
MMEProteinP08473 (Uniprot-TrEMBL)
Prorenin-Prorenin ReceptorComplexR-HSA-2065393 (Reactome)
REN ProteinP00797 (Uniprot-TrEMBL)
REN(24-406) ProteinP00797 (Uniprot-TrEMBL)
Renin:Prorenin ReceptorComplexR-HSA-2022360 (Reactome)
ReninComplexR-HSA-2990850 (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.
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
aliskirenMetaboliteCHEBI:601027 (ChEBI)
benazepril
benazeprilat
hydrolysed ACEIsComplexR-ALL-9619018 (Reactome)
hydrolysed ACEIsComplexR-ALL-9619021 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ACE(30-1232)R-HSA-9614933 (Reactome)
ACE(30-1232)mim-catalysisR-HSA-2065355 (Reactome)
ACE(30-1306)mim-catalysisR-HSA-2022398 (Reactome)
ACE(30-1306)mim-catalysisR-HSA-2022405 (Reactome)
ACE2(18-805)mim-catalysisR-HSA-2022378 (Reactome)
ACE2(18-805)mim-catalysisR-HSA-2022379 (Reactome)
ACEI pro-drugsR-HSA-9619024 (Reactome)
ACEIs:ACE(30-1232)ArrowR-HSA-9614933 (Reactome)
ACEIs:ACE(30-1232)TBarR-HSA-2065355 (Reactome)
ACEIsR-HSA-9614933 (Reactome)
AGT(34-40)ArrowR-HSA-2022368 (Reactome)
AGT(34-40)ArrowR-HSA-2022379 (Reactome)
AGT(34-40)ArrowR-HSA-2022396 (Reactome)
AGT(34-40)ArrowR-HSA-2022398 (Reactome)
AGT(34-41)ArrowR-HSA-2022381 (Reactome)
AGT(34-41)ArrowR-HSA-2022383 (Reactome)
AGT(34-41)ArrowR-HSA-2022405 (Reactome)
AGT(34-41)ArrowR-HSA-2022411 (Reactome)
AGT(34-41)ArrowR-HSA-2065355 (Reactome)
AGT(34-41)R-HSA-2022379 (Reactome)
AGT(34-41)R-HSA-2022399 (Reactome)
AGT(34-42)ArrowR-HSA-2022378 (Reactome)
AGT(34-42)ArrowR-HSA-2028294 (Reactome)
AGT(34-42)R-HSA-2022368 (Reactome)
AGT(34-42)R-HSA-2022398 (Reactome)
AGT(34-43)ArrowR-HSA-2022403 (Reactome)
AGT(34-43)ArrowR-HSA-2022412 (Reactome)
AGT(34-43)ArrowR-HSA-2065357 (Reactome)
AGT(34-43)R-HSA-2022378 (Reactome)
AGT(34-43)R-HSA-2022381 (Reactome)
AGT(34-43)R-HSA-2022383 (Reactome)
AGT(34-43)R-HSA-2022396 (Reactome)
AGT(34-43)R-HSA-2022405 (Reactome)
AGT(34-43)R-HSA-2022411 (Reactome)
AGT(34-43)R-HSA-2028294 (Reactome)
AGT(34-43)R-HSA-2065355 (Reactome)
AGT(35-41)ArrowR-HSA-2022399 (Reactome)
AGT(35-41)R-HSA-2022393 (Reactome)
AGT(35-41)R-HSA-8851929 (Reactome)
AGT(36-41)ArrowR-HSA-2022393 (Reactome)
AGT(36-41)ArrowR-HSA-8851929 (Reactome)
AGTR-HSA-2022403 (Reactome)
AGTR-HSA-2022412 (Reactome)
AGTR-HSA-2065357 (Reactome)
ANPEP Dimermim-catalysisR-HSA-2022393 (Reactome)
AOPEP:Zn2+mim-catalysisR-HSA-8851929 (Reactome)
AlcoholArrowR-HSA-9619024 (Reactome)
CES1 trimermim-catalysisR-HSA-9619024 (Reactome)
CMA1mim-catalysisR-HSA-2022383 (Reactome)
CTSZmim-catalysisR-HSA-2022381 (Reactome)
Carboxypeptidasemim-catalysisR-HSA-2028294 (Reactome)
Cathepsin Gmim-catalysisR-HSA-2022411 (Reactome)
Cl-ArrowR-HSA-2022405 (Reactome)
Cl-ArrowR-HSA-2065355 (Reactome)
ENPEP Dimermim-catalysisR-HSA-2022399 (Reactome)
H2OR-HSA-2022368 (Reactome)
H2OR-HSA-2022378 (Reactome)
H2OR-HSA-2022379 (Reactome)
H2OR-HSA-2022381 (Reactome)
H2OR-HSA-2022383 (Reactome)
H2OR-HSA-2022393 (Reactome)
H2OR-HSA-2022396 (Reactome)
H2OR-HSA-2022398 (Reactome)
H2OR-HSA-2022399 (Reactome)
H2OR-HSA-2022403 (Reactome)
H2OR-HSA-2022405 (Reactome)
H2OR-HSA-2022411 (Reactome)
H2OR-HSA-2022412 (Reactome)
H2OR-HSA-2028294 (Reactome)
H2OR-HSA-2065355 (Reactome)
H2OR-HSA-2065357 (Reactome)
H2OR-HSA-8851929 (Reactome)
H2OR-HSA-9619024 (Reactome)
L-ArgArrowR-HSA-8851929 (Reactome)
MMEmim-catalysisR-HSA-2022368 (Reactome)
MMEmim-catalysisR-HSA-2022396 (Reactome)
Prorenin-Prorenin Receptormim-catalysisR-HSA-2065357 (Reactome)
R-HSA-2022368 (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).
R-HSA-2022378 (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).
R-HSA-2022379 (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).
R-HSA-2022381 (Reactome) Cathepsin Z (cathepsin X) hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) (angiotensin II) (Nagler et al. 2010).
R-HSA-2022383 (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).
R-HSA-2022393 (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.
R-HSA-2022396 (Reactome) Neprilysin hydrolyzes angiotensin-(1-10) (angiotensin I) directly to angiotensin-(1-7) (Rice et al. 2004).
R-HSA-2022398 (Reactome) Angiotensin-converting enzyme (ACE) hydrolyzes angiotensin-(1-9) to yield angiotensin-(1-7) (Rice et al. 2004).
R-HSA-2022399 (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).
R-HSA-2022403 (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).
R-HSA-2022405 (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).
R-HSA-2022411 (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).
R-HSA-2022412 (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).
R-HSA-2028294 (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).
R-HSA-2065355 (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.
R-HSA-2065357 (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).
R-HSA-8851929 (Reactome) Aminopeptidase O (AOPEP, AP-O) is a member of the M1 family of zinc metallopeptidases or gluzincins. AOPEP contains a large catalytic gluzincin domain which has the archetypal metalloprotease zinc-binding site ending in a family-specific Glu residue (HEXXHX[18]E) typical to this family. AOPEP is able to catalyse the hydrolsis of an arginine residue (L-Arg) from angiotensin III (AGT(35-41)) to form angiotensin IV (AGT(36-41)), a bioactive peptide of the renin-angiotensin pathway. AOPEP does not contain a recognisable signal sequence or type II transmembrane domain, indicating that it likely belongs to the cytoplasmic subfamily of gluzincins (Diaz-Perales et al. 2005). AOPEP mRNA transcripts are predominantly detected in the pancreas, placenta, liver, testis, and heart. Expression of the AOPEP in heart and testis could suggest involvement in the regulation of cardiac and male reproductive physiology (Diaz-Perales et al. 2005).
R-HSA-9614933 (Reactome) Angiotensin-converting enzyme (ACE) is a central component of the renin–angiotensin-aldosterone system (RAAS), controlling blood pressure by regulating the fluid volume in the body. It converts the hormone angiotensin I (ATI) to the active vasoconstrictor angiotensin II (ATII). Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors (ACEIs) block the conversion of ATI to ATII, thereby lowering arteriolar resistance and increasing venous capacity. The first ACEI, captopril, was developed from a peptide found in pit viper venom, used by the indiginous Brazilian tribes as an arrowhead poison (Patlak 2004). ACEIs decrease the production of ATII, which prevents aldosterone release from the adrenal cortex. This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This has the effect of decreasing blood volume, leading to decreased blood pressure (Kono et al. 1979, 1982). ACEIs are widely used as pharmaceutical drugs primarily for the treatment of hypertension (elevated blood pressure) and congestive heart failure (Abrams et al. 1984, Johnston et al. 1984, 1986).

ACEIs can be divided into three groups based on their molecular structure; sulfhydryl-containing agents (captopril, zofenopril), dicarboxylate-containing agents (includes enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilizapril and spirapril) and the phosphonate-containing agent fosinopril. Captopril (Capoten), was the first ACE inhibitor developed in 1975 and gaining FDA approval in 1981 (Smith & Vane 2003). Unlike the majority of ACE inhibitors, captopril is not administered as a prodrug (the only other being lisinopril). It is used in the treatment of hypertension and some types of congestive heart failure (Hollenberg 1984, Turini et al. 1983). It is also used to improve survivability after myocardial infarction and to preserve kidney function in diabetic nephropathy. Zofenopril is administered as a prodrug and is metabolized in the liver to the active form zofenoprilat (Jiang et al. 2011, Tian et al. 2015). It is used in the treatment of hypertension and ischemic heart disorders (Nilsson 2007, Ambrosioni 2007).

Enalapril is a prodrug that is metabolized by the liver into the active form enalaprilat (Shioya et al. 1992). It is used to treat hypertension, diabetic nephropathy, and heart failure (Davies et al. 1984, Gomez et al. 1985). Ramipril is an ACE inhibitor (Bunning 1984) which is administered as a prodrug and metabolized by the liver to its active form ramiprilat (Vasmant & Bender 1989). It is used to treat mild to moderate hypertension and congestive heart failure (Frampton & Peters 1995). Quinapril is a second-generation ACE inhibitor, administered as a pro-drug which is converted to its active metabolite, quinaprilat in the liver (Cetnarowski-Cropp 1991). It inhibits plasma ACE activity in studies with healthy volunteers (Sedman & Posvar 1989). Quinapril is used in the treatment of patients with hypertension and congestive heart failure (Plosker & Sorkin 1994). Efficacy is comparable to other ACE inhibitors but with a lower incidence of adverse events or withdrawals than captopril or enalapril (Frank et al. 1990).

Perindopril is an ester prodrug that is metabolized in the liver to its active form perindoprilat. It is used to treat hypertension, heart failure and stable coronary artery disease (Chalmers & MacMahon 2003). Lisinopril was the third ACE inhibitor (after captopril and enalapril) to be approved for clinical use in the treatment of hypertension (Pool et al. 1987) and congestive heart failure (Giles 1989). Chemically, it is the lysine analogue of enalapril. Unlike other ACE inhibitors, it is not a prodrug and is excreted unchanged in the urine (Armayor & Lopez 1988, Noble & Murray 1988). Benazepril is administered as an ester prodrug and metabolized by the liver to its active form benazeprilat (Sioufi et al. 1988). It is used primarily in the treatment of hypertension, congestive heart failure, and heart attacks (Gengo & Brady 1991, Balfour & Goa 1991). Imidapril is an ACE inhibitor (Robinson et al. 2007), administered as a prodrug which is metabolized in the liver to the active form, imidaprilat (Hoogkamer et al. 1997). It is used in the treatment of mild to moderate essential hypertension (Palma-Gamiz et al. 2007) as well as preventing the onset of heart failure in patients after a myocardial infarction (Dolezal 2006).

Trandolapril is a prodrug that is metabolized in the liver to its active form trandolaprilat (Conen & Brunner 1993). Is an ACE inhibitor used to treat hypertension and congestive heart failure (Ducky & Brunner 1992, Diaz & Ducharme 2008). Cilazapril is a prodrug converted to the active drug cilazaprilat in the liver (Deget & Brogden 1991). It is used for the treatment of hypertension and congestive heart failure (Waterfall 1989, Szucs 1991). Cilazapril is branded as Dynorm, Inhibace and Vascace in various countries but is not available in the US. Spirapril is a prodrug metabolized to the active metabolite spiraprilat (Bellissant et al. 1997 ). It is used in the treatment of mild to moderate hypertension, administered once daily due to its long duration of action but with a narrow dose range ((Hayduk & Kraul 1999). Fosinopril is the only member of a phosphinic acid derivative which undergoes rapid hydrolysis mainly in the gastrointestinal mucosa and liver to the active form fosinoprilat (Cur et al. 2007). It is used for the treatment of hypertension and some types of chronic heart failure (Murdoch & McTavish 1992, Davis et al. 1997).

R-HSA-9619024 (Reactome) Mammalian carboxylesterases (CES) are a well conserved family that catalyse the hydrolysis of a vast array of endogenous and exogenous substrates including environmental toxins and drugs. CES-mediated hydrolysis plays an important role in the disposition of a number of widely prescribed therapeutic agents from a diverse range of drug classes including angiotensin-converting enzyme inhibitors (ACEIs). In humans, two carboxylesterases, CES1 and CES2, are important enzymes in drug metabolism (Brzezinski et al. 1994, Pindel et al. 1997). Both are expressed in liver but levels of CE1 are much higher than CE2. Most ACEI prodrugs (except captopril and lisinopril) are administered as esterified prodrugs which are probably susceptible to hydrolysis by CES1 trimer (Thomsen et al. 2014). The resultant active drugs (suffix 'prilat') can inhibit the conversion of angiotensin I to angiotensin II, thereby contributing to the antihypertensive effect of these drugs. Some CES1 genetic variants (eg. G143E) may impair ACEI activation, and consequently affect therapeutic outcomes of ACEI prodrugs (Wang et al. 2016).
R-HSA-9619034 (Reactome) To exert their biological effects on extracellular angiotensin, angiotensin-converting enzyme inhibitors (ACEIs) translocate to the extracellular region by an unknown mechanism (Johnston et al. 1986).
Renin:Prorenin ReceptorArrowR-HSA-2022403 (Reactome)
Renin:Prorenin Receptormim-catalysisR-HSA-2022403 (Reactome)
Reninmim-catalysisR-HSA-2022412 (Reactome)
aliskirenTBarR-HSA-2022403 (Reactome)
aliskirenTBarR-HSA-2022412 (Reactome)
aliskirenTBarR-HSA-2065357 (Reactome)
hydrolysed ACEIsArrowR-HSA-9619024 (Reactome)
hydrolysed ACEIsArrowR-HSA-9619034 (Reactome)
hydrolysed ACEIsR-HSA-9619034 (Reactome)
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