Pathway: Metabolism of Angiotensinogen to Angiotensins
Reactions in pathway: Metabolism of Angiotensinogen to Angiotensins :
Metabolism of Angiotensinogen to Angiotensins
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).
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).
Peptide hormones are cleaved from larger precursors in the secretory system (endoplasmic reticulum, Golgi apparatus, secretory granules) of the cell. After secretion peptide hormones are modified and degraded by extracellular proteases.
Insulin processing occurs in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin by PCSK1 (PC1/3) and PCSK2 to yield insulin, translocation of the granules across the cytosol to the plasma membrane.
During Synthesis, secretion, and deacetylation of Ghrelin, proghrelin is acylated by ghrelin O-acyltransferase and cleaved by PCSK1 to yield the mature acyl ghrelin and C-ghrelin. In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase.
During Metabolism of Angiotensinogen to Angiotensin, Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Two C-terminal amino acid residues of angiotensin I are then 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 and described.
Incretin synthesis, secretion, and inactivation occurs through processing of incretin precursors (preproGLP-1 and preproGIP) by PCSK1. After secretion both incretins (GLP-1 and GIP) can be inactivated by cleavage by DPP4.
Peptide hormone biosynthesis describes processing of glycoprotein hormones (those which include carbohydrate side-chains) and corticotropin.
Insulin processing occurs in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin by PCSK1 (PC1/3) and PCSK2 to yield insulin, translocation of the granules across the cytosol to the plasma membrane.
During Synthesis, secretion, and deacetylation of Ghrelin, proghrelin is acylated by ghrelin O-acyltransferase and cleaved by PCSK1 to yield the mature acyl ghrelin and C-ghrelin. In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase.
During Metabolism of Angiotensinogen to Angiotensin, Renin cleaves angiotensinogen to yield a decapaptide, angiotensin I (angiotensin-1, angiotensin-(1-10)). Two C-terminal amino acid residues of angiotensin I are then 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 and described.
Incretin synthesis, secretion, and inactivation occurs through processing of incretin precursors (preproGLP-1 and preproGIP) by PCSK1. After secretion both incretins (GLP-1 and GIP) can be inactivated by cleavage by DPP4.
Peptide hormone biosynthesis describes processing of glycoprotein hormones (those which include carbohydrate side-chains) and corticotropin.
Metabolism of proteins, as annotated here, covers the full life cycle of a protein from its synthesis to its posttranslational modification and degradation, at various levels of specificity. Protein synthesis is accomplished through the process of Translation of an mRNA sequence into a polypeptide chain. Protein folding is achieved through the function of molecular chaperones which recognize and associate with proteins in their non-native state and facilitate their folding by stabilizing the conformation of productive folding intermediates (Young et al. 2004). Following translation, many newly formed proteins undergo Post-translational protein modification, essentially irreversible covalent modifications critical for their mature locations and functions (Knorre et al. 2009), including gamma carboxylation, synthesis of GPI-anchored proteins, asparagine N-linked glycosylation, O-glycosylation, SUMOylation, ubiquitination, deubiquitination, RAB geranylgeranylation, methylation, carboxyterminal post-translational modifications, neddylation, and phosphorylation. Peptide hormones are synthesized as parts of larger precursor proteins whose cleavage in the secretory system (endoplasmic reticulum, Golgi apparatus, secretory granules) is annotated in Peptide hormone metabolism. After secretion, peptide hormones are modified and degraded by extracellular proteases (Chertow, 1981 PMID:6117463). Protein repair enables the reversal of damage to some amino acid side chains caused by reactive oxygen species. Pulmonary surfactants are lipids and proteins that are secreted by the alveolar cells of the lung that decrease surface tension at the air/liquid interface within the alveoli to maintain the stability of pulmonary tissue (Agassandian and Mallampalli 2013). Nuclear regulation, transport, metabolism, reutilization, and degradation of surfactant are described in the Surfactant metabolism pathway. Amyloid fiber formation, the accumulation of mostly extracellular deposits of fibrillar proteins, is associated with tissue damage observed in numerous diseases including late phase heart failure (cardiomyopathy) and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's.