id: MODULE:renin_angiotensin_cascade title: Renin-angiotensin cascade — renin (with the (pro)renin receptor) cleavage of angiotensinogen, ACE or chymase/cathepsin G formation of angiotensin II, the ACE2/neprilysin/PRCP angiotensin-(1-7) arm acting on MAS1, and the ENPEP/ANPEP aminopeptidase arm to angiotensin III and IV description: >- The renin-angiotensin cascade is the extracellular proteolytic pathway that generates the family of angiotensin peptide hormones from a single precursor, angiotensinogen (AGT), a liver-secreted serpin-fold glycoprotein that does none of the cleaving itself. Renin (REN), an aspartic endopeptidase released by the juxtaglomerular cells of the kidney, cleaves the N-terminal Leu-Val bond of angiotensinogen and releases the inactive decapeptide angiotensin I; this is the rate-limiting step. On tissue surfaces renin and its zymogen prorenin bind the (pro)renin receptor ATP6AP2, which raises renin's catalytic efficiency and lets prorenin act without proteolytic activation. The zinc peptidyl-dipeptidase angiotensin-converting enzyme (ACE), anchored on endothelial cells and also shed into plasma, removes the C-terminal His-Leu dipeptide of angiotensin I to give the octapeptide angiotensin II, the principal effector, which acts on the AT1 and AT2 receptors. In tissues, angiotensin II is also formed independently of ACE by the mast-cell serine protease chymase (CMA1) and by neutrophil cathepsin G (CTSG). A counter-regulatory arm converts the pressor peptides into angiotensin-(1-7): the monocarboxypeptidase ACE2 removes the C-terminal phenylalanine of angiotensin II (its preferred substrate) and the C-terminal leucine of angiotensin I to give angiotensin-(1-9); neprilysin (MME) cleaves angiotensin I and angiotensin-(1-9) to angiotensin-(1-7), as ACE also does for angiotensin-(1-9); and the lysosomal prolylcarboxypeptidase PRCP releases the C-terminal phenylalanine of angiotensin II and III. Angiotensin-(1-7) is the agonist of the G protein-coupled receptor MAS1 and opposes angiotensin II with vasodilator and antiproliferative actions. A third arm trims angiotensin II from the N terminus: glutamyl aminopeptidase (aminopeptidase A, ENPEP) removes Asp1 to give angiotensin III, which still acts on the AT1 and AT2 receptors and dominates in the brain renin-angiotensin system, and alanyl aminopeptidase (aminopeptidase N, ANPEP) removes Arg1 of angiotensin III to give angiotensin IV. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000492 title: renin-angiotensin cascade pathway statement: >- The module boundary, members and topology follow the RGD Pathway Ontology record and interactive diagram for this term. The record states that "The inactive angiotensinogen precursor Agt is the sole substrate of renin aspartyl protease", that "Receptor-bound renin has a higher catalytic activity than renin in solution", that "The product of renin is the inactive peptide AgtI, in turn the substrate of Ace", that AgtIII results "from the cleavage of AgtII by the aminopeptidase Enpep", that Anpep "generates AgtIV from AgtIII", and that "the Agt1-7 peptide can be generated from AgtII through the action of Ace2 or from AgtI through the action of the neutral endopeptidease Mme" and "signals through its own receptor Mas1". The diagram draws Agt->AgtI->AgtII->AgtIII->AgtIV, AgtI and AgtII->Agt(1-7), Agt(1-7) with Mas1, Atp6ap2 and Igf2r associated with Ren, Renbp -| Ren, AgtII and AgtIII with Agtr1a/Agtr1b/Agtr2 and AgtIV with Lnpep. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000492.yaml). Human genes RGD curates to PW:0000492: ACE ACE2 AGT AGTR1 AGTR2 ANPEP ATP6AP2 CMA1 CPA3 CTSA CTSG ENPEP IGF2R LNPEP MAS1 MME NLN REN RENBP RNPEP THOP1. - source_id: GO:0002003 title: angiotensin maturation statement: >- The GO process mapped to PW:0000492 (skos:closeMatch) in the project's curated mappings (projects/RGD_PATHWAY_ONTOLOGY/data/pw_go_curated.sssom.yaml), verified in go-basic 2026-07-26 as current (not obsolete), defined as conversion of angiotensinogen into mature angiotensin in the blood, is_a GO:0016486 peptide hormone processing and part_of GO:0002002 regulation of angiotensin levels in blood. It is the module concept and is placed on the protease annotons (and on the (pro)renin receptor cofactor), never on AGT. - source_id: gomodel:6246724f00000549 title: Renin-angiotensin pathway (Human) statement: >- Production human GO-CAM (cached under gocams/6246724f00000549/) and the RGD triage's best-overlap model for PW:0000492. It models REN aspartic-type endopeptidase activity (GO:0004190) and ACE peptidyl-dipeptidase activity (GO:0008241), each part_of GO:0002003 angiotensin maturation and each with has_input AGT (UniProtKB:P01019); REN directly positively regulates ACE, ACE is causally upstream of AGT hormone activity (GO:0005179), and AGT hormone activity is upstream of AGTR1 angiotensin type I receptor activity. This module's REN and ACE annotons carry its activities as gocam_associations; AGT appears in it as the protease input and as the hormone, exactly the two roles AGT has here, and the AGT and AGTR1 activities are already linked from modules/angiotensin_ii_receptor_signaling.yaml. - source_id: PMID:12045255 title: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. statement: >- Expression cloning of the (pro)renin receptor (ATP6AP2): receptor binding increases renin's catalytic efficiency on angiotensinogen. The basis for the ATP6AP2 annoton. supporting_text: The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I - source_id: PMID:15283675 title: Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. statement: >- Kinetic comparison of ACE, ACE2 and neprilysin on the angiotensin peptides; frames the angiotensin-(1-7) part as a set of competing routes whose balance depends on enzyme levels. supporting_text: with the levels of ACE, ACE2 and NEP dictating whether vasoconstriction or vasodilation will predominate - source_id: PMID:12829792 title: Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. statement: Identifies MAS1 as the angiotensin-(1-7) receptor, the basis for part 5. supporting_text: these findings identify Mas as a functional receptor for Ang-(1-7) notes: >- Derived from the RGD Pathway Ontology term PW:0000492 (renin-angiotensin cascade pathway) through the RGD_PATHWAY_ONTOLOGY project (seed in projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml), mapped to GO:0002003 angiotensin maturation. PW:0000492 is the only PW evidence source_id: the module covers the proteolytic cascade. The diagram's receptor-signalling sub-pathways (PW:0000244, PW:0000527, PW:0000528 and the angiotensin III branches PW:0000457, PW:0000530, PW:0000531) and the angiotensin IV and angiotensin-(1-7) signalling pathways (PW:0000458, PW:0000529) are mentioned in prose but are not evidence here; the angiotensin II ones are the evidence of modules/angiotensin_ii_receptor_signaling.yaml. (1) BOUNDARY WITH ANGIOTENSIN II RECEPTOR SIGNALLING. This module is the part that modules/angiotensin_ii_receptor_signaling.yaml deliberately left out (its note 1). The receptor step is part 3, a module_ref to that module, and is not re-modelled; the AGT Angiotensin-2 hormone annoton, AGTR1 and AGTR2 live there. Angiotensin III is routed to the same module because it acts on the same two receptors. (2) AGT IS THE SUBSTRATE, NOT A PARTICIPANT (CLAUDE.md worked example, PR #2972). GO:0002003 is_a GO:0016486 peptide hormone processing, so the term names whatever does the cleaving. Angiotensinogen supplies no residue beyond the bond that is cut, positions nothing and catalyses nothing; renin, ACE and the other peptidases perform every step. AGT therefore appears (a) as the substrate (has_input) of every protease annoton, matching the has_input AGT edges on REN and ACE in gomodel:6246724f00000549, and (b) as the hormone source of angiotensin-(1-7) acting on MAS1 in part 5, paralleling the Angiotensin-2 hormone annoton of the receptor module. It carries no GO:0002003 process anywhere in this file. QuickGO (November 2026) confirms human AGT has no GO:0002003 row; its gene review records protease binding and hormone activity as core functions. The substrate peptides are named by AGT residue range in preferred_term (angiotensin I 25-34, angiotensin-(1-9) 25-33, angiotensin II 25-32, angiotensin-(1-7) 25-31, angiotensin III 26-32, angiotensin IV 27-32, the PEPTIDE features of the AGT UniProt entry) and grounded to the AGT accession. (3) THE (PRO)RENIN RECEPTOR. ATP6AP2 is included in the renin step as a cofactor annoton, not as a protease: it binds renin and prorenin, raises renin's catalytic efficiency about fourfold and makes prorenin active without proteolysis (PMID:12045255; Reactome R-HSA-2022403, R-HSA-2065357). Unlike AGT it does contribute to the work of the step, which is why GOA's two IDA rows placing it in GO:0002003 are kept (the ATP6AP2 gene review accepts both) and why the comparator logic of note 2 does not exclude it. Its function here is GO:0016504 peptidase activator activity on renin, the capacity the cascade uses, rather than the GO:0004888 transmembrane signaling receptor activity of its gene review's core function, which is the out-of-scope ERK signalling. GOA has no experimental MF row for it other than bare protein binding, which is not used. Its renin-triggered ERK signalling and its V-ATPase accessory role are outside the module. Whether receptor binding is physiologically important for angiotensin generation in vivo is debated, which is recorded as a knowledge gap. (4) MOLECULAR FUNCTIONS. Chosen from each protein's experimental GOA rows in QuickGO (November 2026): REN GO:0004190 (EXP/IDA PMID:12045255 and older kinetic papers); ACE GO:0008241 (EXP, IDA PMID:11432860, PMID:1320019); ACE2 GO:0004180 (IDA PMID:10924499, PMID:10969042, PMID:15283675; its single IDA GO:0008241 row was not used because on the angiotensins it acts only as a carboxypeptidase; the zinc metallo- child GO:0004181 was considered, but its only human ACE2 row is an IEA transfer from the mouse ortholog, so the IDA-supported parent is kept); MME GO:0004222 (EXP/IDA); CMA1 GO:0004252 (IDA, IBA; EXP rows are to the parent terms endopeptidase and serine-type peptidase activity); CTSG GO:0004252 (EXP/IDA); ENPEP GO:0004230 (EXP PMID:23888046); ANPEP GO:0070006 (IBA; experimental rows only TAS aminopeptidase activity); PRCP GO:0004185 (TAS PMID:28321); MAS1 GO:0001595 angiotensin receptor activity (IBA/ISS, supported here by PMID:12829792), in preference to its TAS row for angiotensin type II receptor activity (PMID:3419518), a 1988 row that predates the identification of angiotensin-(1-7) as its ligand and looks like a possible upstream error worth checking; it is not used. GO:0005515 protein binding is never used. (5) GO:0002003 ON THE ARMS. GOA places GO:0002003 on ACE2 (IBA, IC), MME, PRCP and PREP (IEA), ENPEP and ANPEP (IBA), and CMA1 and CTSG (TAS, Reactome). The term's definition (conversion of angiotensinogen into mature angiotensin) covers each active angiotensin, so it is used on every protease annoton. Some of these enzymes also degrade angiotensins (neprilysin and ACE on angiotensin II and angiotensin-(1-7)), and that catabolic side is mentioned in role descriptions but not modelled as a separate step; GO has no angiotensin catabolic process term. (6) ALTERNATIVE PROTEASES AND WHAT WAS LEFT OUT. Chymase and cathepsin G are modelled as variants of the angiotensin II step (Reactome R-HSA-2022383, R-HSA-2022411); CMA1 and CTSG are on RGD's gene list. Neprilysin, PRCP and ACE are variants of the angiotensin-(1-7) step. PRCP is not on RGD's list but is the classical "angiotensinase C" with direct biochemical evidence (PMID:28321). Prolyl endopeptidase (PREP) was requested as a candidate but is left out: its only GO:0002003 row is IEA by orthology and no cached source documents its action on human angiotensins, so it stays context. Cathepsin D (CTSD) has renin-like activity on angiotensinogen in vitro but is not on RGD's list and no cached source was checked for it, so it is not a variant of the renin step. Other RGD-listed genes left out, by symbol: CTSA (cathepsin A; its gene review models a lysosomal serine carboxypeptidase and deamidase with no angiotensin-specific evidence cached), CPA3 (mast-cell carboxypeptidase A3, Reactome R-HSA-2028294 angiotensin I to angiotensin-(1-9), a minor side reaction with no human experimental GO row checked), cathepsin Z (Reactome R-HSA-2022381, not on RGD's list), NLN, THOP1 and RNPEP (oligopeptidases and arginyl aminopeptidase that RGD inherits from KEGG map04614 by IEA, with no reaction drawn on the RGD diagram), IGF2R (a renin and prorenin clearance receptor, which removes rather than performs the step), RENBP (renin-binding protein, now known to be N-acylglucosamine 2-epimerase; renin inhibition is a historical in vitro observation), LNPEP (IRAP, drawn by RGD as the angiotensin IV receptor; its gene review models it as a metalloaminopeptidase acting on peptide hormones, the angiotensin IV receptor claim is contested, and angiotensin IV signalling PW:0000458 is a separate pathway), and MRGPRD with the decarboxylated peptides angiotensin A and alamandine (Reactome R-HSA-9944540, R-HSA-9944473; the decarboxylase is unknown). AGTR1 and AGTR2 are in the referenced receptor module. (7) GO-CAM LINKS. gomodel:6246724f00000549 is linked on the REN and ACE (angiotensin II step) annotons. No production GO-CAM in gocams/index.tsv models ATP6AP2, CMA1, CTSG, MME, PRCP, ENPEP or ANPEP. ACE2 appears only in SARS-CoV-2 entry models (virus receptor activity) and MAS1 only in a CXCL17 chemokine model (gomodel:68fac5ed00003102); neither concerns angiotensin processing, so they are not linked. ACE's bradykinin-degradation activity (gomodel:6246724f00000632) belongs to modules/kallikrein_kinin_cascade.yaml. (8) GROUNDING. UniProt accessions come from genes/human//-uniprot.txt for AGT and ATP6AP2 and from UniProt REST (reviewed human entries) for the rest. GO ids and labels were checked against .cache/rgd_pw/go-basic.obo (2026-07-26). Gene reviews exist for AGT, ATP6AP2, CTSA, CTSD and LNPEP only; REN, ACE, ACE2, CMA1, CTSG, MME, PRCP, ENPEP, ANPEP and MAS1 have none yet, which is curation follow-up for the project plan. PANTHER ids are omitted: every participant is a concrete human gene product and no family id was checked. module: id: renin_angiotensin_cascade label: Renin-angiotensin cascade module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation description: >- Conversion of angiotensinogen into mature angiotensin peptides in the blood; a child of GO:0016486 peptide hormone processing. The GO term mapped to PW:0000492 (skos:closeMatch). context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane description: >- ACE, ACE2, neprilysin and the two aminopeptidases are ectoenzymes whose active sites face the extracellular space, and the (pro)renin receptor and MAS1 are plasma-membrane receptors; all act on peptides in the same extracellular compartment as soluble renin, chymase and cathepsin G. parts: - order: 1 role: angiotensin I formation from angiotensinogen node: id: ras_renin_cleavage label: Renin cleavage of angiotensinogen to angiotensin I, enhanced by the (pro)renin receptor module_type: REACTION description: >- The rate-limiting, committed step. Renin cleaves angiotensinogen (AGT), the substrate, to release the decapeptide angiotensin I (AGT residues 25-34). On cell surfaces the (pro)renin receptor ATP6AP2 binds renin and prorenin and increases the efficiency of the same cleavage; it is a cofactor and receptor, not a second protease. annotons: - id: ren_angiotensinogen_cleavage label: Renin aspartic-type endopeptidase activity on angiotensinogen participant: selector_type: GENE_PRODUCT gene_product: preferred_term: REN term: id: UniProtKB:P00797 label: Renin function: preferred_term: aspartic-type endopeptidase activity term: id: GO:0004190 label: aspartic-type endopeptidase activity substrates: - preferred_term: angiotensinogen (releasing angiotensin I, AGT 25-34) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Circulating renin from the juxtaglomerular cells performs the only cleavage that angiotensinogen itself undergoes; angiotensinogen is the input, not a participant. This is the has_input relation of the REN activity in gomodel:6246724f00000549. evidence: - source_id: Reactome:R-HSA-2022412 statement: Circulating renin cleaves angiotensinogen to angiotensin I. supporting_text: Renin in the bloodstream hydrolyzes angiotensinogen to yield angiotensin-(1-10) (angiotensin I). - source_id: PMID:12045255 statement: >- Receptor-bound renin converts angiotensinogen to angiotensin I with fourfold higher catalytic efficiency, showing renin as the catalyst. supporting_text: The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I gocam_associations: - model: gomodel:6246724f00000549 activity: gomodel:6246724f00000549/6246724f00000562 title: REN aspartic-type endopeptidase activity (GO:0004190), has_input AGT, part of GO:0002003 - id: atp6ap2_renin_receptor label: (Pro)renin receptor binding renin and prorenin and enhancing angiotensin I generation participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ATP6AP2 term: id: UniProtKB:O75787 label: Renin receptor function: preferred_term: peptidase activator activity term: id: GO:0016504 label: peptidase activator activity targets: - preferred_term: renin and prorenin (REN), the peptidase it activates term: id: UniProtKB:P00797 label: Renin processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Cell-surface receptor for renin and prorenin. Binding raises renin's catalytic efficiency about fourfold and makes prorenin catalytically active without removal of its prosegment, so it contributes to the cleavage that renin performs. It also signals to ERK1/2 independently of angiotensin II, which is outside this module. The function asserted here is the work it does in the cascade, peptidase activator activity on renin (PMID:12045255), not the GO:0004888 transmembrane signaling receptor activity that is the core function in the ATP6AP2 gene review (genes/human/ATP6AP2/): that capacity is the out-of-scope ERK signalling. GOA has no experimental row for either term (only bare protein binding by IPI and an IEA receptor row), so this is an authored function. Its larger housekeeping role as a V-ATPase accessory subunit is not part of this cascade. evidence: - source_id: PMID:12045255 statement: Cells expressing the cloned receptor bind renin and prorenin specifically. supporting_text: Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding - source_id: PMID:12045255 statement: The receptor places angiotensin II generation at the cell surface. supporting_text: This discovery emphasizes the role of the cell surface in angiotensin II generation - source_id: Reactome:R-HSA-2065357 statement: Prorenin acquires protease activity only when bound to the receptor. supporting_text: Prorenin is inactive when not bound to the (pro)renin receptor. - order: 2 role: angiotensin II formation from angiotensin I node: id: ras_angiotensin_ii_formation label: Conversion of angiotensin I to angiotensin II by ACE, or by chymase or cathepsin G in tissues module_type: REACTION description: >- Angiotensin I is cleaved at its Phe8-His9 bond to the octapeptide angiotensin II (AGT 25-32). ACE, a dipeptidyl carboxypeptidase that removes His-Leu, is the canonical and ACE-inhibitor-sensitive route; the mast-cell chymase CMA1 and neutrophil cathepsin G (CTSG) are serine endopeptidases that make the same product at the same bond in tissues, independently of ACE. variant_sets: - id: ras_angiotensin_ii_forming_proteases label: Angiotensin II-forming proteases axis: protease and tissue context selection: ONE_OR_MORE notes: >- ACE is the systemic enzyme, at the endothelial surface and shed into plasma. Chymase and cathepsin G are released from mast-cell and neutrophil granules and form angiotensin II locally, notably in the human heart and vessel wall, which is why ACE inhibitors do not abolish tissue angiotensin II. Each variant alone satisfies the step. variants: - id: ras_ace_variant label: ACE (angiotensin-converting enzyme) module_type: REACTION annotons: - id: ace_angiotensin_i_conversion label: ACE peptidyl-dipeptidase activity converting angiotensin I to angiotensin II participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ACE term: id: UniProtKB:P12821 label: Angiotensin-converting enzyme function: preferred_term: peptidyl-dipeptidase activity term: id: GO:0008241 label: peptidyl-dipeptidase activity substrates: - preferred_term: angiotensin I (AGT 25-34) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Both catalytic domains (N and C) are zinc peptidyl-dipeptidases that remove the C-terminal His-Leu of angiotensin I; the enzyme acts membrane-bound on endothelium and as the shed soluble form in plasma. The same activity inactivates bradykinin, which is modelled in modules/kallikrein_kinin_cascade.yaml. evidence: - source_id: PMID:11432860 statement: Both ACE domains are peptidyl dipeptidases that hydrolyse angiotensin I. supporting_text: Both the N- and C-terminal domains are peptidyl dipeptidases. - source_id: PMID:11432860 statement: Angiotensin I is ACE's decapeptide substrate. supporting_text: Hydrolysis by ACE of its decapeptide substrate Ang I is increased by Cl(-) - source_id: Reactome:R-HSA-2022405 statement: ACE is located at the plasma membrane of endothelial cells. supporting_text: ACE is found at the plasma membrane of endothelial cells. gocam_associations: - model: gomodel:6246724f00000549 activity: gomodel:6246724f00000549/6246724f00000550 title: ACE peptidyl-dipeptidase activity (GO:0008241), has_input AGT, part of GO:0002003 - id: ras_chymase_variant label: Chymase (CMA1), mast-cell route module_type: REACTION annotons: - id: cma1_angiotensin_i_conversion label: Chymase serine-type endopeptidase activity converting angiotensin I to angiotensin II participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CMA1 term: id: UniProtKB:P23946 label: Chymase function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: angiotensin I (AGT 25-34) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- ACE-independent tissue route: chymase released from degranulating mast cells cleaves angiotensin I at the same Phe8-His9 bond, faster than ACE. CMA1 carries serine-type endopeptidase activity by IDA and GO:0002003 by TAS from this Reactome reaction. evidence: - source_id: Reactome:R-HSA-2022383 statement: Chymase converts angiotensin I to angiotensin II faster than ACE. supporting_text: Chymase hydrolyzes angiotensin-(1-10) (angiotensin) to yield angiotensin-(1-8) (angiotensin II) at a higher rate than does angiotensin-converting enzyme - id: ras_cathepsin_g_variant label: Cathepsin G (CTSG), neutrophil route module_type: REACTION annotons: - id: ctsg_angiotensin_i_conversion label: Cathepsin G serine-type endopeptidase activity converting angiotensin I to angiotensin II participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CTSG term: id: UniProtKB:P08311 label: Cathepsin G function: preferred_term: serine-type endopeptidase activity term: id: GO:0004252 label: serine-type endopeptidase activity substrates: - preferred_term: angiotensin I (AGT 25-34) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Neutrophil granule serine protease that forms angiotensin II from angiotensin I at inflammatory sites, more actively when bound to the neutrophil surface. CTSG carries serine-type endopeptidase activity by EXP/IDA and GO:0002003 by TAS from this Reactome reaction. evidence: - source_id: Reactome:R-HSA-2022411 statement: Cathepsin G converts angiotensin I to angiotensin II. supporting_text: Cathepsin G hydrolyzes angiotensin-(1-10) (angiotensin I) to yield angiotensin-(1-8) - source_id: Reactome:R-HSA-2022411 statement: Membrane-bound cathepsin G on neutrophils is more active than the soluble enzyme. supporting_text: Cathepsin bound to the plasma membrane of neutrophils has a higher activity than does soluble cathepsin G - order: 3 role: angiotensin II and angiotensin III receptor signalling (by reference) node: id: ras_angiotensin_receptor_signaling label: Angiotensin II (and angiotensin III) action on AT1 and AT2 receptors (by reference) description: >- Included by reference to the angiotensin II receptor signalling module, which models the Angiotensin-2 peptide (AGT hormone activity) as the ligand of AGTR1 and AGTR2 and both receptor branches. Angiotensin III engages the same two receptors with broadly similar effects (RGD PW:0000457, PW:0000530, PW:0000531), so it is routed into the same referenced module rather than re-modelled. module_ref: angiotensin_ii_receptor_signaling - order: 4 role: angiotensin-(1-7) formation (counter-regulatory arm) node: id: ras_angiotensin_1_7_formation label: Formation of angiotensin-(1-7) and angiotensin-(1-9) by ACE2, neprilysin, ACE and prolylcarboxypeptidase module_type: REACTION description: >- The counter-regulatory arm converts the pressor peptides into angiotensin-(1-7) (AGT 25-31). ACE2 removes the C-terminal Phe of angiotensin II (its best substrate) and, much less efficiently, the C-terminal Leu of angiotensin I to give angiotensin-(1-9) (AGT 25-33). Neprilysin cleaves angiotensin I and angiotensin-(1-9) directly to angiotensin-(1-7), and ACE also converts angiotensin-(1-9) to angiotensin-(1-7). The lysosomal prolylcarboxypeptidase PRCP releases the C-terminal Phe of angiotensin II and III. Which enzyme dominates depends on the tissue and on their relative levels. variant_sets: - id: ras_angiotensin_1_7_forming_enzymes label: Angiotensin-(1-7)-forming peptidases axis: peptidase and substrate route selection: ONE_OR_MORE notes: >- Three routes: from angiotensin II by ACE2 (dominant; kcat/Km 2.2e6 M-1 s-1 in PMID:15283675) or PRCP; from angiotensin I directly by neprilysin; and from angiotensin I via angiotensin-(1-9) by ACE2 followed by neprilysin or ACE. Each route alone yields angiotensin-(1-7). variants: - id: ras_ace2_variant label: ACE2 (from angiotensin II, and angiotensin I to angiotensin-(1-9)) module_type: REACTION annotons: - id: ace2_angiotensin_ii_cleavage label: ACE2 carboxypeptidase activity converting angiotensin II to angiotensin-(1-7) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ACE2 term: id: UniProtKB:Q9BYF1 label: Angiotensin-converting enzyme 2 function: preferred_term: carboxypeptidase activity term: id: GO:0004180 label: carboxypeptidase activity substrates: - preferred_term: angiotensin II (AGT 25-32) and angiotensin I (AGT 25-34) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Captopril-insensitive zinc monocarboxypeptidase. Its efficient reaction is angiotensin II to angiotensin-(1-7); the reaction on angiotensin I to angiotensin-(1-9) is several hundred-fold weaker. Both are one activity (single C-terminal residue removal) and are kept on one annoton. Its separate role as the SARS-CoV-2 receptor is outside this module. evidence: - source_id: PMID:15283675 statement: ACE2 efficiently cleaves angiotensin II to angiotensin-(1-7). supporting_text: Ang II was cleaved efficiently by ACE2 to Ang (1-7) - source_id: PMID:10969042 statement: ACE2 removes the C-terminal Leu of angiotensin I to give angiotensin-(1-9). supporting_text: Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9 - source_id: PMID:10924499 statement: On the angiotensins ACE2 acts only as a carboxypeptidase. supporting_text: In the hydrolysis of the angiotensins, ACEH functions exclusively as a carboxypeptidase. - source_id: PMID:10969042 statement: ACE2 is insensitive to ACE inhibitors. supporting_text: ACE2 is not inhibited by lisinopril or captopril. - id: ras_neprilysin_variant label: Neprilysin (MME) (from angiotensin I or angiotensin-(1-9)) module_type: REACTION annotons: - id: mme_angiotensin_cleavage label: Neprilysin metalloendopeptidase activity converting angiotensin I and angiotensin-(1-9) to angiotensin-(1-7) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MME term: id: UniProtKB:P08473 label: Neprilysin function: preferred_term: metalloendopeptidase activity term: id: GO:0004222 label: metalloendopeptidase activity substrates: - preferred_term: angiotensin I (AGT 25-34) and angiotensin-(1-9) (AGT 25-33) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Neutral endopeptidase 24.11 cuts the Pro7-Phe8 bond of angiotensin I and angiotensin-(1-9), bypassing angiotensin II. It also degrades angiotensin II to smaller fragments, so it is both a source of angiotensin-(1-7) and an angiotensinase. MME carries metalloendopeptidase activity by EXP/IDA; its GO:0002003 row is IEA. evidence: - source_id: PMID:15283675 statement: Neprilysin efficiently cleaves angiotensin I to angiotensin-(1-7). supporting_text: Ang I was effectively cleaved by NEP to Ang (1-7) - source_id: PMID:15283675 statement: Angiotensin-(1-9) is a better neprilysin substrate than an ACE substrate. supporting_text: Ang (1-9) was a better substrate for NEP than ACE - id: ras_prcp_variant label: Prolylcarboxypeptidase (PRCP) (from angiotensin II and III) module_type: REACTION annotons: - id: prcp_angiotensin_ii_cleavage label: Prolylcarboxypeptidase serine-type carboxypeptidase activity on angiotensin II and III participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PRCP term: id: UniProtKB:P42785 label: Lysosomal Pro-X carboxypeptidase function: preferred_term: serine-type carboxypeptidase activity term: id: GO:0004185 label: serine-type carboxypeptidase activity substrates: - preferred_term: angiotensin II (AGT 25-32) and angiotensin III (AGT 26-32) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: lysosome term: id: GO:0005764 label: lysosome role_description: >- "Angiotensinase C": cleaves the Pro7-Phe8 bond of angiotensin II and III. Its acid pH optimum places it chiefly in lysosomes, although it retains half its activity on angiotensin III at neutral pH, and it is also found on the endothelial surface where it activates prekallikrein (modules/kallikrein_kinin_cascade.yaml). Not on RGD's PW:0000492 gene list; included as an alternative angiotensin-(1-7) source on this biochemical evidence. Its GO:0002003 row is IEA only. Lysosome is its only location here because the cited angiotensin cleavage was characterised at the acid optimum; the endothelial-surface pool is noted but no cached source shows angiotensin cleavage there. evidence: - source_id: PMID:28321 statement: Purified human kidney PRCP cleaves the C-terminal Pro-Phe bond of angiotensin II. supporting_text: The enzyme cleaved benzyloxycarbonyl (Cbz)-Pro-Phe, representing the COOH-terminal end of angiotensin II - source_id: PMID:28321 statement: PRCP has an acid pH optimum but keeps half its activity at neutral pH. supporting_text: The enzyme had an acid pH optimum (4.5 to 5.5), but hydrolyzed angiotensin III at pH 7 at 50% of the optimal rate. - id: ras_ace_angiotensin_1_9_variant label: ACE (from angiotensin-(1-9)) module_type: REACTION annotons: - id: ace_angiotensin_1_9_cleavage label: ACE peptidyl-dipeptidase activity converting angiotensin-(1-9) to angiotensin-(1-7) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ACE term: id: UniProtKB:P12821 label: Angiotensin-converting enzyme function: preferred_term: peptidyl-dipeptidase activity term: id: GO:0008241 label: peptidyl-dipeptidase activity substrates: - preferred_term: angiotensin-(1-9) (AGT 25-33) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The same ACE dipeptidyl-carboxypeptidase activity as in the angiotensin II step, here removing Phe8-His9 from angiotensin-(1-9) produced by ACE2. ACE also degrades angiotensin-(1-7) further, so it both makes and removes the heptapeptide. evidence: - source_id: Reactome:R-HSA-2022398 statement: ACE converts angiotensin-(1-9) to angiotensin-(1-7). supporting_text: Angiotensin-converting enzyme (ACE) hydrolyzes angiotensin-(1-9) to yield angiotensin-(1-7) - order: 5 role: angiotensin-(1-7) action on the MAS1 receptor node: id: ras_angiotensin_1_7_mas_signaling label: Angiotensin-(1-7) activation of the MAS1 G protein-coupled receptor module_type: REGULATORY_STEP description: >- Angiotensin-(1-7) is the endogenous agonist of the G protein-coupled receptor MAS1, through which it opposes angiotensin II (vasodilation, natriuresis and antiproliferative effects). No separate module exists for Mas signalling, so the ligand-receptor step is modelled here; its downstream effectors are not. annotons: - id: agt_angiotensin_1_7_hormone label: Angiotensin-(1-7) peptide hormone (MAS1 ligand) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AGT (Angiotensin 1-7 peptide) term: id: UniProtKB:P01019 label: Angiotensinogen function: preferred_term: hormone activity term: id: GO:0005179 label: hormone activity targets: - preferred_term: MAS1 term: id: UniProtKB:P04201 label: Proto-oncogene Mas locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- The active species is the Angiotensin 1-7 peptide (AGT residues 25-31), cleaved from angiotensinogen by the enzymes of the previous part. This is the only activity attributed to AGT in this module: it is the hormone source, as in modules/angiotensin_ii_receptor_signaling.yaml for Angiotensin-2, and it is otherwise only the input (substrate) of the protease annotons. It carries no angiotensin maturation process term. evidence: - source_id: PMID:12829792 statement: Angiotensin-(1-7) binds Mas-expressing cells and elicits a cellular response. supporting_text: Ang-(1-7) binds to Mas-transfected cells and elicits arachidonic acid release - id: mas1_angiotensin_1_7_receptor label: MAS1 angiotensin receptor activity (angiotensin-(1-7) receptor) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MAS1 term: id: UniProtKB:P04201 label: Proto-oncogene Mas function: preferred_term: angiotensin receptor activity term: id: GO:0001595 label: angiotensin receptor activity processes: - preferred_term: G protein-coupled receptor signaling pathway term: id: GO:0007186 label: G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The angiotensin-(1-7) receptor. Mas deletion abolishes angiotensin-(1-7) binding in kidney and its antidiuretic and aortic relaxant actions. GOA carries GO:0001595 for MAS1 by IBA and ISS and GPCR activity by IDA; the process is left at GPCR signalling because GO:0038166 is defined by angiotensin II, not angiotensin-(1-7). evidence: - source_id: PMID:12829792 statement: Mas deletion abolishes angiotensin-(1-7) binding in mouse kidney. supporting_text: genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys - source_id: PMID:12829792 statement: Mas is a functional receptor for angiotensin-(1-7). supporting_text: these findings identify Mas as a functional receptor for Ang-(1-7) - order: 6 role: angiotensin III formation node: id: ras_angiotensin_iii_formation label: Aminopeptidase A (ENPEP) removal of Asp1 from angiotensin II to give angiotensin III module_type: REACTION description: >- Glutamyl aminopeptidase (aminopeptidase A) removes the N-terminal Asp of angiotensin II to give angiotensin III (AGT 26-32), which still activates the AT1 and AT2 receptors and is the main pressor angiotensin in the brain. annotons: - id: enpep_angiotensin_ii_cleavage label: ENPEP glutamyl aminopeptidase activity on angiotensin II participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ENPEP term: id: UniProtKB:Q07075 label: Glutamyl aminopeptidase function: preferred_term: glutamyl aminopeptidase activity term: id: GO:0004230 label: glutamyl aminopeptidase activity substrates: - preferred_term: angiotensin II (AGT 25-32) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Calcium-modulated zinc ectopeptidase specific for acidic N-terminal residues; it removes Asp1 but not the following Arg2. ENPEP carries glutamyl aminopeptidase activity by EXP (PMID:23888046) and GO:0002003 by IBA. evidence: - source_id: PMID:23888046 statement: Aminopeptidase A removes the N-terminal Asp, not the adjacent Arg, of angiotensin II. supporting_text: zinc-dependent aminopeptidase A (APA) up-regulates blood pressure by specifically cleaving the N-terminal aspartate, but not the adjacent arginine, from angiotensin II - source_id: Reactome:R-HSA-2022399 statement: ENPEP converts angiotensin II to angiotensin III. supporting_text: Aminopeptidase A (APA, ENPEP) hydrolyzes the N-terminal amino acid of angiotensin-(1-8) (angiotensin II) to yield angiotensin-(2-8) (angiotensin III) - order: 7 role: angiotensin IV formation node: id: ras_angiotensin_iv_formation label: Aminopeptidase N (ANPEP) removal of Arg1 from angiotensin III to give angiotensin IV module_type: REACTION description: >- Alanyl aminopeptidase (aminopeptidase N, CD13) removes the N-terminal Arg of angiotensin III to give the hexapeptide angiotensin IV (AGT 27-32), which has little AT1/AT2 activity. annotons: - id: anpep_angiotensin_iii_cleavage label: ANPEP metalloaminopeptidase activity on angiotensin III participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ANPEP term: id: UniProtKB:P15144 label: Aminopeptidase N function: preferred_term: metalloaminopeptidase activity term: id: GO:0070006 label: metalloaminopeptidase activity substrates: - preferred_term: angiotensin III (AGT 26-32) term: id: UniProtKB:P01019 label: Angiotensinogen processes: - preferred_term: angiotensin maturation term: id: GO:0002003 label: angiotensin maturation locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Broad-specificity zinc ectopeptidase. The direct evidence for this reaction is on the rabbit renal enzyme (Reactome R-NUL-2022369); human ANPEP carries metalloaminopeptidase activity and GO:0002003 by IBA, and aminopeptidase activity by TAS, with no human experimental row for the angiotensin reaction itself. evidence: - source_id: Reactome:R-NUL-2022369 statement: Renal aminopeptidase N converts angiotensin III to angiotensin IV (rabbit enzyme). supporting_text: ANPEP from rabbit renal membranes hydrolyzes angiotensin III to yield angiotensin IV. connections: - source: ras_renin_cleavage target: ras_angiotensin_ii_formation connection_type: PROVIDES_INPUT_FOR description: >- Angiotensin I made by renin is the substrate of ACE (or chymase or cathepsin G). In gomodel:6246724f00000549 the REN activity directly positively regulates the ACE activity. - source: ras_renin_cleavage target: ras_angiotensin_1_7_formation connection_type: PROVIDES_INPUT_FOR description: >- Angiotensin I is also the substrate of neprilysin (to angiotensin-(1-7)) and of ACE2 (to angiotensin-(1-9)). - source: ras_angiotensin_ii_formation target: ras_angiotensin_receptor_signaling connection_type: PROVIDES_INPUT_FOR description: >- Angiotensin II is the agonist of AT1 and AT2; in gomodel:6246724f00000549 the ACE activity is causally upstream of AGT hormone activity, which is upstream of AGTR1. - source: ras_angiotensin_ii_formation target: ras_angiotensin_1_7_formation connection_type: PROVIDES_INPUT_FOR description: >- Angiotensin II is the preferred substrate of ACE2 and a substrate of PRCP, which divert it into angiotensin-(1-7). - source: ras_angiotensin_ii_formation target: ras_angiotensin_iii_formation connection_type: PROVIDES_INPUT_FOR description: Angiotensin II is the substrate of aminopeptidase A. - source: ras_angiotensin_1_7_formation target: ras_angiotensin_1_7_mas_signaling connection_type: PROVIDES_INPUT_FOR description: Angiotensin-(1-7) is the agonist of MAS1. - source: ras_angiotensin_iii_formation target: ras_angiotensin_receptor_signaling connection_type: PROVIDES_INPUT_FOR description: >- Angiotensin III engages the same AT1 and AT2 receptors (RGD PW:0000530 and PW:0000531). - source: ras_angiotensin_iii_formation target: ras_angiotensin_iv_formation connection_type: PROVIDES_INPUT_FOR description: Angiotensin III is the substrate of aminopeptidase N. knowledge_gaps: - gap_statement: >- Whether the (pro)renin receptor ATP6AP2 contributes measurably to angiotensin generation in vivo is unresolved. It increases renin's catalytic efficiency and activates prorenin in cell systems, but the plasma concentrations of renin and prorenin are far below the receptor's binding affinity, and its essential V-ATPase role confounds loss-of-function experiments, so the angiotensin-dependent contribution has not been separated from its other functions. gap_kind: - BIOLOGY status: OPEN significance: >- It decides whether tissue angiotensin II generation is a receptor-scaffolded surface process or simply soluble renin acting locally. provenance: - reference_id: PMID:12045255 supporting_text: This discovery emphasizes the role of the cell surface in angiotensin II generation - gap_statement: >- The relative in vivo flux of angiotensin I and angiotensin II through ACE, chymase, ACE2, neprilysin and prolylcarboxypeptidase in a given tissue is not known. Kinetic constants are measured on purified enzymes, but the outcome depends on local enzyme amounts, membrane localisation and competition for the same peptides, which current measurements do not resolve in intact tissue. gap_kind: - BIOLOGY status: OPEN significance: >- It determines whether vasoconstrictor or vasodilator angiotensins predominate locally and why ACE inhibition leaves residual tissue angiotensin II. provenance: - reference_id: PMID:15283675 supporting_text: the flux of peptides through the RAS is complex