Metabolism of angiotensinogen to angiotensins (Homo sapiens)
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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.
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.
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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).