Ace encodes somatic angiotensin I-converting enzyme (ACE, kininase II, EC 3.4.15.1), a zinc- and chloride-dependent peptidyl-dipeptidase of the peptidase M2 family. The somatic enzyme is a type I transmembrane ectoenzyme with two homologous extracellular catalytic domains (N- and C-domain), anchored in the plasma membrane of vascular endothelium and of absorptive epithelia (renal proximal tubule and intestinal brush border); juxtamembrane shedding releases a soluble form that circulates in plasma and is present in cerebrospinal fluid. ACE removes C-terminal dipeptides from oligopeptides. Its principal physiological actions are conversion of angiotensin I to the vasoconstrictor angiotensin II (C-domain preferred) and inactivation of the vasodilator bradykinin, which together raise systemic arterial blood pressure and promote sodium retention within the renin-angiotensin system. It also inactivates or processes other bioactive peptides, including substance P, neurotensin, enkephalins (converting Met-enkephalin-Arg-Phe to Met-enkephalin, with effects on synaptic plasticity), angiotensin-(1-7), gonadoliberin, and the haematopoietic regulator N-acetyl-Ser-Asp-Lys-Pro (AcSDKP, N-domain preferred), and in the intestine contributes to digestion of prolyl peptides. An alternative intragenic promoter produces a testis-specific isoform (germinal ACE) with only the C-domain, expressed in spermatocytes and on the sperm midpiece and shed during epididymal transit, which is required for male fertility through unidentified substrates. In the rat, Ace lies at a chromosome 10 blood-pressure locus and is a candidate modifier of hypertensive end-organ damage.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001666 response to hypoxia | IEP PMID:14527966 Regulation of the angiotensin-converting enzyme activity by ... | MARK AS OVER ANNOTATED | Summary: Carotid body ACE activity rises during chronic hypoxia; this is regulation of Ace by hypoxia. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:14527966 ACE activity was markedly increased under the hypoxic stress of 7-, 14-, 21-, and 28-day exposures. |
| GO:0001822 kidney development | IEP PMID:7977726 Regulation of ACE gene expression and plasma levels during r... | KEEP AS NON CORE | Summary: Ace contributes to kidney development through local angiotensin II generation; non-core developmental role. Reason: Ace-null mice (donor evidence for the ISO/ISS rows: mouse IMP PMID:11723129, PMID:12777443, PMID:14757757, PMID:17135368) have hypoplastic renal papilla and medullary defects, the renal phenotype shared by all renin-angiotensin pathway knockouts, so the contribution is real but runs through Ang II production. The rat IEP row (developmental regulation of renal Ace expression) is weak on its own but consistent. Kept as non-core: development is a downstream consequence of the angiotensin-generating activity. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:7977726 In the kidney, they were low and decreased further during growth. |
| GO:0001822 kidney development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ace contributes to kidney development through local angiotensin II generation; non-core developmental role. Reason: Ace-null mice (donor evidence for the ISO/ISS rows: mouse IMP PMID:11723129, PMID:12777443, PMID:14757757, PMID:17135368) have hypoplastic renal papilla and medullary defects, the renal phenotype shared by all renin-angiotensin pathway knockouts, so the contribution is real but runs through Ang II production. The rat IEP row (developmental regulation of renal Ace expression) is weak on its own but consistent. Kept as non-core: development is a downstream consequence of the angiotensin-generating activity. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:7977726 In the kidney, they were low and decreased further during growth. |
| GO:0001822 kidney development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ace contributes to kidney development through local angiotensin II generation; non-core developmental role. Reason: Ace-null mice (donor evidence for the ISO/ISS rows: mouse IMP PMID:11723129, PMID:12777443, PMID:14757757, PMID:17135368) have hypoplastic renal papilla and medullary defects, the renal phenotype shared by all renin-angiotensin pathway knockouts, so the contribution is real but runs through Ang II production. The rat IEP row (developmental regulation of renal Ace expression) is weak on its own but consistent. Kept as non-core: development is a downstream consequence of the angiotensin-generating activity. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:7977726 In the kidney, they were low and decreased further during growth. |
| GO:0001822 kidney development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ace contributes to kidney development through local angiotensin II generation; non-core developmental role. Reason: Ace-null mice (donor evidence for the ISO/ISS rows: mouse IMP PMID:11723129, PMID:12777443, PMID:14757757, PMID:17135368) have hypoplastic renal papilla and medullary defects, the renal phenotype shared by all renin-angiotensin pathway knockouts, so the contribution is real but runs through Ang II production. The rat IEP row (developmental regulation of renal Ace expression) is weak on its own but consistent. Kept as non-core: development is a downstream consequence of the angiotensin-generating activity. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:7977726 In the kidney, they were low and decreased further during growth. |
| GO:0001822 kidney development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ace contributes to kidney development through local angiotensin II generation; non-core developmental role. Reason: Ace-null mice (donor evidence for the ISO/ISS rows: mouse IMP PMID:11723129, PMID:12777443, PMID:14757757, PMID:17135368) have hypoplastic renal papilla and medullary defects, the renal phenotype shared by all renin-angiotensin pathway knockouts, so the contribution is real but runs through Ang II production. The rat IEP row (developmental regulation of renal Ace expression) is weak on its own but consistent. Kept as non-core: development is a downstream consequence of the angiotensin-generating activity. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:7977726 In the kidney, they were low and decreased further during growth. |
| GO:0002003 angiotensin maturation | IBA GO_REF:0000033 | ACCEPT | Summary: Ace converts angiotensin I to angiotensin II by removing the C-terminal His-Leu dipeptide; this is its defining physiological activity. Reason: Core function. Rat ACE in CSF converts Ang I to Ang II (PMID:2172462), and the curated UniProt function names the conversion as the major role of the enzyme. ACE is the protease that performs this processing step, so it is a genuine participant in angiotensin maturation (unlike the substrate angiotensinogen). Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II |
| GO:0002003 angiotensin maturation | ISO GO_REF:0000121 | ACCEPT | Summary: Ace converts angiotensin I to angiotensin II by removing the C-terminal His-Leu dipeptide; this is its defining physiological activity. Reason: Core function. Rat ACE in CSF converts Ang I to Ang II (PMID:2172462), and the curated UniProt function names the conversion as the major role of the enzyme. ACE is the protease that performs this processing step, so it is a genuine participant in angiotensin maturation (unlike the substrate angiotensinogen). Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II |
| GO:0002003 angiotensin maturation | ISO GO_REF:0000121 | ACCEPT | Summary: Ace converts angiotensin I to angiotensin II by removing the C-terminal His-Leu dipeptide; this is its defining physiological activity. Reason: Core function. Rat ACE in CSF converts Ang I to Ang II (PMID:2172462), and the curated UniProt function names the conversion as the major role of the enzyme. ACE is the protease that performs this processing step, so it is a genuine participant in angiotensin maturation (unlike the substrate angiotensinogen). Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II |
| GO:0002003 angiotensin maturation | ISS GO_REF:0000024 | ACCEPT | Summary: Ace converts angiotensin I to angiotensin II by removing the C-terminal His-Leu dipeptide; this is its defining physiological activity. Reason: Core function. Rat ACE in CSF converts Ang I to Ang II (PMID:2172462), and the curated UniProt function names the conversion as the major role of the enzyme. ACE is the protease that performs this processing step, so it is a genuine participant in angiotensin maturation (unlike the substrate angiotensinogen). Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II |
| GO:0002446 neutrophil mediated immunity | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Mouse-derived acts-upstream annotation from myeloid ACE overexpression (PMID:17082641 donor); not a process ACE executes. Reason: The donor phenotype comes from mice with ectopic/over-expression of ACE in myeloid cells, where enhanced neutrophil function follows by an unresolved mechanism. ACE's established activity is peptide processing; there is no evidence that rat Ace performs a step of neutrophil-mediated immunity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity |
| GO:0003081 regulation of systemic arterial blood pressure by renin-angiotensin | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is the converting enzyme of the renin-angiotensin system and so a direct participant in RAS control of systemic arterial blood pressure. Reason: Core process. ACE catalyses the Ang I to Ang II step of the renin-angiotensin system and inactivates bradykinin; antisense knock-down of Ace lowers blood pressure in SHR (PMID:10506486). Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. |
| GO:0003084 positive regulation of systemic arterial blood pressure | IBA GO_REF:0000033 | ACCEPT | Summary: Ace raises systemic arterial blood pressure by generating angiotensin II and inactivating bradykinin. Reason: Core process with rat genetic-perturbation support: retroviral ACE antisense lowered blood pressure in SHR (PMID:10506486). The IBA node and the human/mouse orthologs agree. Supporting Evidence: PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0003084 positive regulation of systemic arterial blood pressure | IEA GO_REF:0000117 | ACCEPT | Summary: Ace raises systemic arterial blood pressure by generating angiotensin II and inactivating bradykinin. Reason: Core process with rat genetic-perturbation support: retroviral ACE antisense lowered blood pressure in SHR (PMID:10506486). The IBA node and the human/mouse orthologs agree. Supporting Evidence: PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0003084 positive regulation of systemic arterial blood pressure | IMP PMID:10506486 Sustained inhibition of angiotensin I-converting enzyme (ACE... | ACCEPT | Summary: Ace raises systemic arterial blood pressure by generating angiotensin II and inactivating bradykinin. Reason: Core process with rat genetic-perturbation support: retroviral ACE antisense lowered blood pressure in SHR (PMID:10506486). The IBA node and the human/mouse orthologs agree. Supporting Evidence: PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0003084 positive regulation of systemic arterial blood pressure | ISO GO_REF:0000121 | ACCEPT | Summary: Ace raises systemic arterial blood pressure by generating angiotensin II and inactivating bradykinin. Reason: Core process with rat genetic-perturbation support: retroviral ACE antisense lowered blood pressure in SHR (PMID:10506486). The IBA node and the human/mouse orthologs agree. Supporting Evidence: PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0003779 actin binding | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Actin binding transferred from human ACE isoform 1; no supporting donor annotation is now retrievable and ACE has only a ~30-residue cytoplasmic tail. Reason: ACE is a type I ectoenzyme whose catalytic domains face the extracellular space; actin binding is not part of its described function in UniProt. A QuickGO query (2026-10-28) found no current human ACE annotation to GO:0003779, so the ISO donor appears stale. Retaining actin binding as a function of rat Ace over-reaches the evidence. Propagation Review Root cause: SOURCE STALE OR MISSING Sources checked: UniProtKB:P12821 SOURCE STALE OR MISSING No current human ACE annotation to actin binding was found in QuickGO (2026-10-28). UniProtKB:P12821-1 SOURCE STALE OR MISSING No current human ACE annotation to actin binding was found in QuickGO (2026-10-28). Supporting Evidence: UniProtKB:P47820 Single-pass type I membrane protein |
| GO:0004175 endopeptidase activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ACE can cleave internally in blocked peptides (e.g. release of the N-terminal tripeptide of LH-RH), a secondary endopeptidase-like activity. Reason: Human ACE hydrolyses N- and C-terminally blocked LH-RH, including cleavage of the Trp-Ser bond to release pGlu-His-Trp (PMID:2983326), and degrades amyloid-beta. These are real but secondary to the dipeptidyl carboxypeptidase activity. Supporting Evidence: PMID:2983326 human ACE, although it is named peptidyl dipeptidase or dipeptidyl carboxypeptidase, can cleave a protected peptide at the NH2 or COOH terminus UniProtKB:P47820 Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones |
| GO:0004181 metallocarboxypeptidase activity | ISO GO_REF:0000121 | UNDECIDED | Summary: Metallocarboxypeptidase activity transferred from mouse (donor IDA PMID:18158355, PMID:27649628); ACE is classified as a peptidyl-dipeptidase (EC 3.4.15.1), not a single-residue carboxypeptidase. Reason: GO:0004181 asserts release of a single C-terminal residue. The canonical ACE reaction releases a C-terminal dipeptide and is already captured by GO:0008241. The mouse donor papers (antigen-peptide trimming by ACE) were not available to verify whether single-residue release was shown, so the row is left undecided rather than removed. Propagation Review Root cause: UNRESOLVED Sources checked: MGI:MGI:87874 UNRESOLVED Mouse donor IDA (PMID:18158355, PMID:27649628) not read; canonical ACE chemistry is dipeptide release (EC 3.4.15.1). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity |
| GO:0004222 metalloendopeptidase activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Zinc-dependent endopeptidase-like cleavage of blocked peptides (LH-RH, amyloid-beta) by ACE; secondary to its peptidyl-dipeptidase activity. Reason: ACE is a zinc metallopeptidase and human ACE cleaves blocked peptides internally (PMID:2983326). Kept as non-core, secondary to GO:0008241. Supporting Evidence: PMID:2983326 human ACE, although it is named peptidyl dipeptidase or dipeptidyl carboxypeptidase, can cleave a protected peptide at the NH2 or COOH terminus UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. |
| GO:0004222 metalloendopeptidase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Zinc-dependent endopeptidase-like cleavage of blocked peptides (LH-RH, amyloid-beta) by ACE; secondary to its peptidyl-dipeptidase activity. Reason: ACE is a zinc metallopeptidase and human ACE cleaves blocked peptides internally (PMID:2983326). Kept as non-core, secondary to GO:0008241. Supporting Evidence: PMID:2983326 human ACE, although it is named peptidyl dipeptidase or dipeptidyl carboxypeptidase, can cleave a protected peptide at the NH2 or COOH terminus UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000828256 SUPPORTS TRANSFER Donor claim is correct and transfers to rat Ace, whose soluble form is measured in rat serum and CSF. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005576 extracellular region | IDA PMID:19307186 Angiotensin-converting enzyme is a modifier of hypertensive ... | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005576 extracellular region | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005576 extracellular region | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005576 extracellular region | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005576 extracellular region | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Ace is shed from the cell surface as a soluble enzyme active in serum, plasma and CSF, so extracellular region is a correct location for the circulating enzyme. Reason: The location is correct and core to the circulating enzyme's function. Serum Ace activity was measured directly in the rat (PMID:19307186) and a soluble peptidyl dipeptidase is present in rat CSF (PMID:2172462); UniProt describes release into blood plasma after juxtamembrane shedding. Extracellular space (GO:0005615), the usual refinement, is obsolete in the current GO release, and no live descendant of extracellular region describes a soluble plasma or CSF enzyme better (the membrane-anchored pool is captured separately by external side of plasma membrane), so extracellular region is retained. Supporting Evidence: PMID:19307186 Serum Ace activity (Fig. 6a) and Western blot analysis (Fig. 6b) revealed that both Ace activity and Ace protein are lower in noninduced Ren2.L than Ren2.F. PMID:2172462 demonstrated the presence in CSF of a peptidyl dipeptidase UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Intracellular Ace immunoreactivity in neurons (by similarity to mouse); peripheral to the cell-surface/extracellular site of action. Reason: GO cytoplasm includes the secretory pathway, where the type I membrane protein is synthesised and trafficked; the UniProt note records neuronal cytoplasmic staining. The location is plausible but not where the catalytic function acts. Supporting Evidence: UniProtKB:P47820 Detected in both cell membrane and cytoplasm in neurons. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Intracellular Ace immunoreactivity in neurons (by similarity to mouse); peripheral to the cell-surface/extracellular site of action. Reason: GO cytoplasm includes the secretory pathway, where the type I membrane protein is synthesised and trafficked; the UniProt note records neuronal cytoplasmic staining. The location is plausible but not where the catalytic function acts. Supporting Evidence: UniProtKB:P47820 Detected in both cell membrane and cytoplasm in neurons. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Intracellular Ace immunoreactivity in neurons (by similarity to mouse); peripheral to the cell-surface/extracellular site of action. Reason: GO cytoplasm includes the secretory pathway, where the type I membrane protein is synthesised and trafficked; the UniProt note records neuronal cytoplasmic staining. The location is plausible but not where the catalytic function acts. Supporting Evidence: UniProtKB:P47820 Detected in both cell membrane and cytoplasm in neurons. |
| GO:0005764 lysosome | ISO GO_REF:0000121 | UNDECIDED | Summary: Lysosome location transferred from human ACE (donor IDA PMID:11076943); the cached abstract concerns ACE shedding and does not mention lysosomes. Reason: Under the root-organelle policy an ISO row must be checked against its source. The donor paper is abstract-only here and the abstract describes stalk cleavage and secretion, not lysosomal localization; lysosomal delivery of internalized ACE is plausible but not verifiable from available text. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P12821 UNRESOLVED Human donor IDA PMID:11076943 is abstract-only here and the abstract does not mention lysosomes. Supporting Evidence: PMID:11076943 is a type 1 ectoprotein, which is released from the plasma membrane by a proteolytic cleavage occurring in the stalk sequence adjacent to the membrane anchor |
| GO:0005768 endosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ACE is co-internalized with the bradykinin B2 receptor into endosomes after agonist stimulation (human donor, PMID:17077303). Reason: Endosomal ACE reflects trafficking of the surface enzyme with its partner receptor; real but peripheral to its extracellular catalytic role. Supporting Evidence: PMID:17077303 Bradykinin stimulation cointernalized ACE and B2 receptors. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Somatic Ace is a type I transmembrane ectoenzyme of the plasma membrane (endothelium, brush-border epithelia). Reason: Core location: the catalytic domains are extracellular and the enzyme is anchored by one TM helix; rat intestinal brush-border membranes carry the activity (PMID:2827504). Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane UniProtKB:P47820 Single-pass type I membrane protein PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Somatic Ace is a type I transmembrane ectoenzyme of the plasma membrane (endothelium, brush-border epithelia). Reason: Core location: the catalytic domains are extracellular and the enzyme is anchored by one TM helix; rat intestinal brush-border membranes carry the activity (PMID:2827504). Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane UniProtKB:P47820 Single-pass type I membrane protein PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Somatic Ace is a type I transmembrane ectoenzyme of the plasma membrane (endothelium, brush-border epithelia). Reason: Core location: the catalytic domains are extracellular and the enzyme is anchored by one TM helix; rat intestinal brush-border membranes carry the activity (PMID:2827504). Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane UniProtKB:P47820 Single-pass type I membrane protein PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Somatic Ace is a type I transmembrane ectoenzyme of the plasma membrane (endothelium, brush-border epithelia). Reason: Core location: the catalytic domains are extracellular and the enzyme is anchored by one TM helix; rat intestinal brush-border membranes carry the activity (PMID:2827504). Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane UniProtKB:P47820 Single-pass type I membrane protein PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Somatic Ace is a type I transmembrane ectoenzyme of the plasma membrane (endothelium, brush-border epithelia). Reason: Core location: the catalytic domains are extracellular and the enzyme is anchored by one TM helix; rat intestinal brush-border membranes carry the activity (PMID:2827504). Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane UniProtKB:P47820 Single-pass type I membrane protein PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Somatic Ace is a type I transmembrane ectoenzyme of the plasma membrane (endothelium, brush-border epithelia). Reason: Core location: the catalytic domains are extracellular and the enzyme is anchored by one TM helix; rat intestinal brush-border membranes carry the activity (PMID:2827504). Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane UniProtKB:P47820 Single-pass type I membrane protein PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Somatic Ace is a type I transmembrane ectoenzyme of the plasma membrane (endothelium, brush-border epithelia). Reason: Core location: the catalytic domains are extracellular and the enzyme is anchored by one TM helix; rat intestinal brush-border membranes carry the activity (PMID:2827504). Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane UniProtKB:P47820 Single-pass type I membrane protein PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MODIFY | Summary: Proteolysis is correct but uninformative; ACE's proteolysis is the processing and inactivation of peptide hormones. Reason: InterPro2GO mapping to a root process term. The supported specific descendant is angiotensin maturation (GO:0002003), already accepted in this review. Proposed replacements: angiotensin maturation Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin |
| GO:0006518 peptide metabolic process | IMP PMID:10642323 Release of angiotensin-(1-7) from the rat hindlimb: influenc... | MODIFY | Summary: Ace degrades angiotensin-(1-7) in rat vasculature; the precise term is peptide catabolic process. Reason: PMID:10642323 shows ACE inhibition increases Ang-(1-7) recovery from the perfused hindlimb, consistent with ACE-mediated degradation of the heptapeptide. Peptide metabolic process is correct but general; refined to peptide catabolic process (GO:0043171). Proposed replacements: peptide catabolic process Supporting Evidence: PMID:10642323 The release of Ang-(1-7) is significantly influenced by inhibition of ACE, which may reflect both increased substrate (Ang I) levels and reduced metabolism of the peptide. |
| GO:0007283 spermatogenesis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Testicular ACE is needed for sperm fertilizing ability, not for formation of spermatozoa (mouse acts-upstream donor PMID:17135368). Reason: Germinal ACE is expressed in spermatocytes and placed on the sperm midpiece, then totally shed in the epididymis (PMID:12444051); its loss impairs male fertility through sperm function, while spermatogenesis proceeds. The substrates required are unknown. Spermatogenesis over-states the role. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 The identity of substrates that are needed for male fertility is unknown. PMID:12444051 the rodent germinal ACE is released from the testicular sperm membrane when sperm enter the epididymis |
| GO:0007565 female pregnancy | IEP PMID:17977916 ACE2 and ANG-(1-7) in the rat uterus during early and late g... | UNDECIDED | Summary: IEP annotation to female pregnancy from a study whose abstract reports ACE2, not ACE, changes in the gestating rat uterus. Reason: The cached abstract measures angiotensin peptides and ACE2; Ace data may be in the full text, which is not available. The term would in any case rest on expression evidence only. Left undecided rather than asserting mis-attribution. Supporting Evidence: PMID:17977916 ACE2 mRNA increased in the uterus of early pregnant compared with virgin rats |
| GO:0008217 regulation of blood pressure | IDA PMID:1750504 Angiotensin-converting enzyme inhibitor versus angiotensin I... | MODIFY | Summary: Ace regulates blood pressure through the renin-angiotensin system; refine to the systemic arterial RAS terms. Reason: Correct but general. The specific supported descendants are regulation of systemic arterial blood pressure by renin-angiotensin (GO:0003081) and positive regulation of systemic arterial blood pressure (GO:0003084), both accepted here. Rat genetic support: Ace at the Bp1 QTL (PMID:1655275), antisense lowers BP (PMID:10506486). The IDA row from PMID:1750504 (balloon injury, smooth muscle migration) is not itself blood-pressure evidence. Proposed replacements: regulation of systemic arterial blood pressure by renin-angiotensin positive regulation of systemic arterial blood pressure Supporting Evidence: PMID:1655275 is closely linked to the rat gene encoding angiotensin-converting enzyme (ACE) PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. |
| GO:0008217 regulation of blood pressure | ISO GO_REF:0000121 | MODIFY | Summary: Ace regulates blood pressure through the renin-angiotensin system; refine to the systemic arterial RAS terms. Reason: Correct but general. The specific supported descendants are regulation of systemic arterial blood pressure by renin-angiotensin (GO:0003081) and positive regulation of systemic arterial blood pressure (GO:0003084), both accepted here. Rat genetic support: Ace at the Bp1 QTL (PMID:1655275), antisense lowers BP (PMID:10506486). The IDA row from PMID:1750504 (balloon injury, smooth muscle migration) is not itself blood-pressure evidence. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:87874 SUPPORTS TRANSFER Donor claim is correct and transfers to rat Ace; only the term granularity is refined. Proposed replacements: regulation of systemic arterial blood pressure by renin-angiotensin positive regulation of systemic arterial blood pressure Supporting Evidence: PMID:1655275 is closely linked to the rat gene encoding angiotensin-converting enzyme (ACE) PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. |
| GO:0008217 regulation of blood pressure | TAS PMID:1655275 Genetic mapping of a gene causing hypertension in the stroke... | MODIFY | Summary: Ace regulates blood pressure through the renin-angiotensin system; refine to the systemic arterial RAS terms. Reason: Correct but general. The specific supported descendants are regulation of systemic arterial blood pressure by renin-angiotensin (GO:0003081) and positive regulation of systemic arterial blood pressure (GO:0003084), both accepted here. Rat genetic support: Ace at the Bp1 QTL (PMID:1655275), antisense lowers BP (PMID:10506486). The IDA row from PMID:1750504 (balloon injury, smooth muscle migration) is not itself blood-pressure evidence. Proposed replacements: regulation of systemic arterial blood pressure by renin-angiotensin positive regulation of systemic arterial blood pressure Supporting Evidence: PMID:1655275 is closely linked to the rat gene encoding angiotensin-converting enzyme (ACE) PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. |
| GO:0008233 peptidase activity | IDA PMID:12500972 Novel natural peptide substrates for endopeptidase 24.15, ne... | MODIFY | Summary: Ace is a peptidase whose specific activity is peptidyl-dipeptidase (dipeptidyl carboxypeptidase) activity. Reason: Correct but general; the specific supported term is GO:0008241. The IDA rows (PMID:12500972, PMID:18077343) concern hemopressin-family peptides, which interact with ACE and are degraded by it according to UniProt. Proposed replacements: peptidyl-dipeptidase activity Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:12500972 Three of these peptides (PVNFKFLSH, VVYPWTQRY, and LVVYPWTQRY) were synthesized and shown to interact with ep24.15, ep24.16, and ACE UniProtKB:P47820 Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin |
| GO:0008233 peptidase activity | IDA PMID:18077343 Hemopressin is an inverse agonist of CB1 cannabinoid recepto... | MODIFY | Summary: Ace is a peptidase whose specific activity is peptidyl-dipeptidase (dipeptidyl carboxypeptidase) activity. Reason: Correct but general; the specific supported term is GO:0008241. The IDA rows (PMID:12500972, PMID:18077343) concern hemopressin-family peptides, which interact with ACE and are degraded by it according to UniProt. Proposed replacements: peptidyl-dipeptidase activity Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:12500972 Three of these peptides (PVNFKFLSH, VVYPWTQRY, and LVVYPWTQRY) were synthesized and shown to interact with ep24.15, ep24.16, and ACE UniProtKB:P47820 Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin |
| GO:0008233 peptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Ace is a peptidase whose specific activity is peptidyl-dipeptidase (dipeptidyl carboxypeptidase) activity. Reason: Correct but general; the specific supported term is GO:0008241. The IDA rows (PMID:12500972, PMID:18077343) concern hemopressin-family peptides, which interact with ACE and are degraded by it according to UniProt. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:87874 SUPPORTS TRANSFER Donor claim is correct and transfers to rat Ace; only the term granularity is refined. Proposed replacements: peptidyl-dipeptidase activity Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:12500972 Three of these peptides (PVNFKFLSH, VVYPWTQRY, and LVVYPWTQRY) were synthesized and shown to interact with ep24.15, ep24.16, and ACE UniProtKB:P47820 Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin |
| GO:0008233 peptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Ace is a peptidase whose specific activity is peptidyl-dipeptidase (dipeptidyl carboxypeptidase) activity. Reason: Correct but general; the specific supported term is GO:0008241. The IDA rows (PMID:12500972, PMID:18077343) concern hemopressin-family peptides, which interact with ACE and are degraded by it according to UniProt. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12821 SUPPORTS TRANSFER Donor claim is correct and transfers to rat Ace; only the term granularity is refined. Proposed replacements: peptidyl-dipeptidase activity Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:12500972 Three of these peptides (PVNFKFLSH, VVYPWTQRY, and LVVYPWTQRY) were synthesized and shown to interact with ep24.15, ep24.16, and ACE UniProtKB:P47820 Acts as a regulator of cannabinoid signaling pathway by mediating degradation of hemopressin |
| GO:0008237 metallopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Ace is a zinc metallopeptidase of the M2 family with two HEXXH zinc active sites. Reason: GO:0008241 peptidyl-dipeptidase activity is not a descendant of metallopeptidase activity, so this term carries independent, correct information on catalytic mechanism and is as specific as GO allows on that axis. Supporting Evidence: UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. UniProtKB:P47820 Belongs to the peptidase M2 family. |
| GO:0008237 metallopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Ace is a zinc metallopeptidase of the M2 family with two HEXXH zinc active sites. Reason: GO:0008241 peptidyl-dipeptidase activity is not a descendant of metallopeptidase activity, so this term carries independent, correct information on catalytic mechanism and is as specific as GO allows on that axis. Supporting Evidence: UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. UniProtKB:P47820 Belongs to the peptidase M2 family. |
| GO:0008237 metallopeptidase activity | IMP PMID:11299220 Pathways of bradykinin degradation in blood and plasma of no... | ACCEPT | Summary: Ace is a zinc metallopeptidase of the M2 family with two HEXXH zinc active sites. Reason: GO:0008241 peptidyl-dipeptidase activity is not a descendant of metallopeptidase activity, so this term carries independent, correct information on catalytic mechanism and is as specific as GO allows on that axis. Supporting Evidence: UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. UniProtKB:P47820 Belongs to the peptidase M2 family. |
| GO:0008237 metallopeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is a zinc metallopeptidase of the M2 family with two HEXXH zinc active sites. Reason: GO:0008241 peptidyl-dipeptidase activity is not a descendant of metallopeptidase activity, so this term carries independent, correct information on catalytic mechanism and is as specific as GO allows on that axis. Supporting Evidence: UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. UniProtKB:P47820 Belongs to the peptidase M2 family. |
| GO:0008237 metallopeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is a zinc metallopeptidase of the M2 family with two HEXXH zinc active sites. Reason: GO:0008241 peptidyl-dipeptidase activity is not a descendant of metallopeptidase activity, so this term carries independent, correct information on catalytic mechanism and is as specific as GO allows on that axis. Supporting Evidence: UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. UniProtKB:P47820 Belongs to the peptidase M2 family. |
| GO:0008238 exopeptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Exopeptidase activity is correct but general for ACE; refine to peptidyl-dipeptidase activity. Reason: GO:0008241 is_a GO:0008238; the specific term is accepted in this review. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12821 SUPPORTS TRANSFER Donor claim is correct and transfers to rat Ace; only the term granularity is refined. Proposed replacements: peptidyl-dipeptidase activity Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity |
| GO:0008240 tripeptidyl-peptidase activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human ACE releases the N-terminal tripeptide pGlu-His-Trp from LH-RH (donor IDA PMID:2983326); a secondary activity. Reason: Direct biochemical evidence in human ACE; rat UniProt records gonadoliberin cleavage by similarity. Secondary to the dipeptidyl carboxypeptidase activity. Supporting Evidence: PMID:2983326 indicating that the Trp-Ser bond is cleaved to release the NH2-terminal tripeptide UniProtKB:P47820 Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones |
| GO:0008241 peptidyl-dipeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | IDA PMID:20487892 Separate metabolic pathways for Leu-enkephalin and Met-enkep... | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | IDA PMID:8292044 Angiotensin converting enzyme and genetic hypertension: clon... | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008241 peptidyl-dipeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Ace is a peptidyl-dipeptidase (dipeptidyl carboxypeptidase, EC 3.4.15.1) removing C-terminal dipeptides from angiotensin I, bradykinin, enkephalin heptapeptide and other peptides. Reason: Core molecular function, directly shown for rat ACE: CSF ACE removes C-terminal dipeptides from bradykinin and converts Ang I (PMID:2172462); synaptic-membrane ACE converts Met-enkephalin-Arg-Phe to Met-enkephalin (PMID:20487892). Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0008270 zinc ion binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ace binds catalytic zinc (two ions in the somatic enzyme). Reason: True cofactor binding required for catalysis; kept as non-core because it is part of the metallopeptidase mechanism rather than a separate function. Supporting Evidence: UniProtKB:P47820 Note=Binds 2 Zn(2+) ions per subunit. |
| GO:0008584 male gonad development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Testis ACE is required for sperm function and male fertility, not for development of the gonad. Reason: The mouse knockout evidence behind these rows shows reduced male fertility with normal testis development; the rat IEP row reflects developmental regulation of germinal ACE expression (PMID:7977726). Gonad development over-states the role. Supporting Evidence: UniProtKB:P47820 Isoform produced by alternative promoter usage that is specifically expressed in spermatocytes and adult testis, and which is required for male fertility. PMID:7977726 ACE gene expression is also developmentally regulated in epithelia and male germinal cells. |
| GO:0008584 male gonad development | IEP PMID:7977726 Regulation of ACE gene expression and plasma levels during r... | MARK AS OVER ANNOTATED | Summary: Testis ACE is required for sperm function and male fertility, not for development of the gonad. Reason: The mouse knockout evidence behind these rows shows reduced male fertility with normal testis development; the rat IEP row reflects developmental regulation of germinal ACE expression (PMID:7977726). Gonad development over-states the role. Supporting Evidence: UniProtKB:P47820 Isoform produced by alternative promoter usage that is specifically expressed in spermatocytes and adult testis, and which is required for male fertility. PMID:7977726 ACE gene expression is also developmentally regulated in epithelia and male germinal cells. |
| GO:0008584 male gonad development | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Testis ACE is required for sperm function and male fertility, not for development of the gonad. Reason: The mouse knockout evidence behind these rows shows reduced male fertility with normal testis development; the rat IEP row reflects developmental regulation of germinal ACE expression (PMID:7977726). Gonad development over-states the role. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Isoform produced by alternative promoter usage that is specifically expressed in spermatocytes and adult testis, and which is required for male fertility. PMID:7977726 ACE gene expression is also developmentally regulated in epithelia and male germinal cells. |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:9495881 Angiotensin I-converting enzyme inhibition but not angiotens... | MARK AS OVER ANNOTATED | Summary: ACE inhibitors induce Ace expression; this is feedback regulation of Ace, not a xenobiotic response executed by Ace. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:9495881 Enalapril, an ACE inhibitor, in the range of 0.3 to 10 mg/kg/day in rats induced dose- and time-dependant increases in plasma ACE up to two to three times control values. |
| GO:0009792 embryo development ending in birth or egg hatching | IMP PMID:1784836 The effect of maternal administration of captopril on fetal ... | MARK AS OVER ANNOTATED | Summary: Maternal captopril reduced implantation and fetal growth; an indirect pharmacological effect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:1784836 The treatment of rats with captopril in doses of 10 and 30 mg/kg, significantly reduced the mean number of implants per litter size and produced intrauterine growth retardation. |
| GO:0009897 external side of plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Somatic ACE is an ectoenzyme with both catalytic domains on the external face of the plasma membrane. Reason: The extracellular topology (residues 36-1265) places the active sites on the external side of the plasma membrane, where the enzyme meets circulating peptides. Supporting Evidence: UniProtKB:P47820 Single-pass type I membrane protein PMID:11076943 is a type 1 ectoprotein, which is released from the plasma membrane by a proteolytic cleavage occurring in the stalk sequence adjacent to the membrane anchor |
| GO:0009925 basal plasma membrane | IDA PMID:2841539 Immunohistochemistry of angiotensin I-converting enzyme in r... | KEEP AS NON CORE | Summary: Ace is on the basal plasma membrane of the ciliary-process internal epithelium in the rat eye. Reason: Direct immuno-EM localization (PMID:2841539); a tissue-specific membrane domain, non-core. Supporting Evidence: PMID:2841539 ACE was found on the basal plasma membrane of the internal epithelium facing the aqueous humor and on vesicles in its vicinity |
| GO:0010608 post-transcriptional regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: From a mouse cardiac ACE overexpression model in which connexin expression changes (donor PMID:25017399); indirect. Reason: Altered gene expression in hearts overexpressing ACE is a downstream consequence of excess angiotensin II, not a gene-regulatory activity of ACE. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity |
| GO:0010629 negative regulation of gene expression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: From a mouse cardiac ACE overexpression model (donor PMID:25017399); indirect effect on gene expression. Reason: As for GO:0010608: ACE has no gene-regulatory activity; expression changes follow from angiotensin II signalling. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity |
| GO:0010814 substance P catabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ACE cleaves substance P, releasing C-terminal di- and tripeptide amides. Reason: Supported by the curated reaction set (by similarity to human ACE). A real but secondary substrate relative to angiotensin I and bradykinin. Supporting Evidence: UniProtKB:P47820 Reaction=substance P + H2O = substance P(1-9) + L-Leu-L-Met-NH2 UniProtKB:P47820 Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins |
| GO:0010814 substance P catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ACE cleaves substance P, releasing C-terminal di- and tripeptide amides. Reason: Supported by the curated reaction set (by similarity to human ACE). A real but secondary substrate relative to angiotensin I and bradykinin. Supporting Evidence: UniProtKB:P47820 Reaction=substance P + H2O = substance P(1-9) + L-Leu-L-Met-NH2 UniProtKB:P47820 Acts as a regulator of synaptic transmission by mediating cleavage of neuropeptide hormones, such as substance P, neurotensin or enkephalins |
| GO:0010815 bradykinin catabolic process | IDA PMID:2172462 Some characteristics of a peptidyl dipeptidase (kininase II)... | ACCEPT | Summary: Ace (kininase II) inactivates bradykinin by sequential removal of C-terminal dipeptides. Reason: Core process with direct rat evidence: rat CSF ACE degrades bradykinin sequentially (PMID:2172462) and ACE accounts for about half of plasma kininase activity in rats (PMID:11299220). Supporting Evidence: PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:11299220 The enzymes ACE, APP, and CPN represented 92% of this kininase activity, with relative contributions of 52, 25, and 16%, respectively. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0010815 bradykinin catabolic process | IMP PMID:11299220 Pathways of bradykinin degradation in blood and plasma of no... | ACCEPT | Summary: Ace (kininase II) inactivates bradykinin by sequential removal of C-terminal dipeptides. Reason: Core process with direct rat evidence: rat CSF ACE degrades bradykinin sequentially (PMID:2172462) and ACE accounts for about half of plasma kininase activity in rats (PMID:11299220). Supporting Evidence: PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:11299220 The enzymes ACE, APP, and CPN represented 92% of this kininase activity, with relative contributions of 52, 25, and 16%, respectively. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0010815 bradykinin catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Ace (kininase II) inactivates bradykinin by sequential removal of C-terminal dipeptides. Reason: Core process with direct rat evidence: rat CSF ACE degrades bradykinin sequentially (PMID:2172462) and ACE accounts for about half of plasma kininase activity in rats (PMID:11299220). Supporting Evidence: PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:11299220 The enzymes ACE, APP, and CPN represented 92% of this kininase activity, with relative contributions of 52, 25, and 16%, respectively. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0010815 bradykinin catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: Ace (kininase II) inactivates bradykinin by sequential removal of C-terminal dipeptides. Reason: Core process with direct rat evidence: rat CSF ACE degrades bradykinin sequentially (PMID:2172462) and ACE accounts for about half of plasma kininase activity in rats (PMID:11299220). Supporting Evidence: PMID:2172462 which sequentially degraded bradykinin (BK) by liberating the carboxy-terminal dipeptides and converted angiotensin I to angiotensin II PMID:11299220 The enzymes ACE, APP, and CPN represented 92% of this kininase activity, with relative contributions of 52, 25, and 16%, respectively. UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response |
| GO:0014910 regulation of smooth muscle cell migration | IDA PMID:1750504 Angiotensin-converting enzyme inhibitor versus angiotensin I... | MARK AS OVER ANNOTATED | Summary: ACE inhibitor benazeprilat reduced smooth muscle cell migration after balloon injury; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:1750504 SMC migration was reduced 94% by the AT1 antagonist and 68% by the ACE inhibitor. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Membrane is correct but general; Ace is a plasma membrane protein. Reason: InterPro2GO mapping; the specific location is plasma membrane (GO:0005886), accepted here. Proposed replacements: plasma membrane Supporting Evidence: UniProtKB:P47820 SUBCELLULAR LOCATION: Cell membrane |
| GO:0030324 lung development | IEP PMID:7977726 Regulation of ACE gene expression and plasma levels during r... | MARK AS OVER ANNOTATED | Summary: Lung ACE rises postnatally as the capillary network develops; expression evidence only. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. The authors attribute the rise to capillary development itself. Supporting Evidence: PMID:7977726 This large increase reflects, at least in part, development of the capillary network. |
| GO:0031100 animal organ regeneration | IMP PMID:22441330 Inhibition of ACE activity contributes to the intestinal str... | MARK AS OVER ANNOTATED | Summary: ACE inhibition altered intestinal adaptation after small bowel resection; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:22441330 The addition of ACE-I to SBS rat resulted in a significant decline in ECs apoptosis. |
| GO:0031404 chloride ion binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Ace binds chloride ions that activate its peptidase activity. Reason: Chloride activation is a defining biochemical property of ACE; kept as non-core cofactor binding. Supporting Evidence: UniProtKB:P47820 Note=Binds 3 chloride ions per subunit. UniProtKB:P47820 The dipeptidyl carboxypeptidase activity is strongly activated by chloride. |
| GO:0031404 chloride ion binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ace binds chloride ions that activate its peptidase activity. Reason: Chloride activation is a defining biochemical property of ACE; kept as non-core cofactor binding. Supporting Evidence: UniProtKB:P47820 Note=Binds 3 chloride ions per subunit. UniProtKB:P47820 The dipeptidyl carboxypeptidase activity is strongly activated by chloride. |
| GO:0031434 mitogen-activated protein kinase kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: MKK7 co-precipitates with ACE in endothelial cells as part of ACE outside-in signalling (human donor IPI PMID:14615289). Reason: Supported for human ACE; a peripheral, signalling-scaffold property of the cytoplasmic tail rather than the core peptidase function. Supporting Evidence: PMID:14615289 Mitogen-activated protein kinase kinase 7 and c-Jun N-terminal kinase (JNK) coprecipitated with ACE |
| GO:0031526 brush border membrane | IDA PMID:2827504 Role of rat intestinal brush-border membrane angiotensin-con... | ACCEPT | Summary: Ace is abundant on the intestinal (and renal) brush-border membrane, where it acts as a digestive and peptide-inactivating peptidase. Reason: Direct rat evidence: activity fractionates with the brush-border membrane and hydrolyses prolyl peptides (PMID:2827504). Supporting Evidence: PMID:2827504 Enzyme activity was associated with the brush-border membrane fraction PMID:2827504 These results show that intestinal brush-border membrane ACE functions as a digestive peptidase |
| GO:0031667 response to nutrient levels | IEP PMID:18389998 Effect of caloric restriction on nitric oxide production, AC... | MARK AS OVER ANNOTATED | Summary: Serum ACE activity falls with caloric restriction; regulation of Ace, not a response executed by it. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:18389998 The serum ACE activity was lower in the CR group. |
| GO:0031711 bradykinin receptor binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ACE forms a complex with the bradykinin B2 receptor at the plasma membrane (human donor, PMID:17077303). Reason: FRET and co-precipitation show ACE-B2 receptor proximity; peripheral to the catalytic function but informative. Supporting Evidence: PMID:17077303 establishing close (within 10 nm) positions of B2 receptors and ACE |
| GO:0031982 vesicle | IDA PMID:2841539 Immunohistochemistry of angiotensin I-converting enzyme in r... | KEEP AS NON CORE | Summary: ACE immunoreactivity on vesicles near the basal membrane of ciliary epithelium. Reason: Direct immuno-EM observation (PMID:2841539); likely trafficking intermediates, non-core. Supporting Evidence: PMID:2841539 ACE was found on the basal plasma membrane of the internal epithelium facing the aqueous humor and on vesicles in its vicinity |
| GO:0032496 response to lipopolysaccharide | IMP PMID:19114890 Effects of an angiotensin-converting enzyme inhibitor on the... | MARK AS OVER ANNOTATED | Summary: Enalapril blunted the LPS inflammatory response in rats; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:19114890 The ACE inhibitor enalapril blocked the LPS-induced inflammatory response |
| GO:0034616 response to laminar fluid shear stress | IEP PMID:9048650 Suppression of angiotensin-converting enzyme expression and ... | MARK AS OVER ANNOTATED | Summary: Shear stress suppresses Ace expression; regulation of Ace, not a response executed by it. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:9048650 These studies suggest that elevations in the level of shear stress alter endothelial cell function by suppressing ACE gene and protein expression in vitro and in vivo. |
| GO:0038166 angiotensin-activated signaling pathway | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ACE produces the ligand (angiotensin II) but is not a component of the receptor-initiated signalling pathway. Reason: The pathway begins with ligand binding to AT1/AT2 receptors. ACE acts upstream by generating the ligand, which is captured by angiotensin maturation. Mouse donor rows come from overexpression/knockout phenotypes (PMID:25017399). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED ACE generates the ligand upstream of the angiotensin receptor pathway; donor phenotype does not place ACE inside the signalling pathway. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin |
| GO:0042310 vasoconstriction | IMP PMID:20204775 Renal vasoconstriction in rats causes a decrease in capillar... | MARK AS OVER ANNOTATED | Summary: Renal-clamp effects were prevented by ACE inhibition; ACE does not perform vasoconstriction. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:20204775 Since the effects of renal vasoconstriction were not seen in rats treated with an inhibitor of angiotensin converting enzyme (ACE) it is suggested they are induced by angiotensin II via activation of the renin-angiotensin system (RAS). |
| GO:0042445 hormone metabolic process | ISO GO_REF:0000121 | MODIFY | Summary: Hormone metabolic process is correct but general; ACE processes angiotensin I and inactivates peptide hormones. Reason: The specific supported terms are angiotensin maturation (GO:0002003, a descendant via peptide hormone processing) and hormone catabolic process (GO:0042447). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12821 SUPPORTS TRANSFER Donor claim is correct and transfers to rat Ace; only the term granularity is refined. Proposed replacements: angiotensin maturation hormone catabolic process Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin UniProtKB:P47820 Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones |
| GO:0042445 hormone metabolic process | ISS GO_REF:0000024 | MODIFY | Summary: Hormone metabolic process is correct but general; ACE processes angiotensin I and inactivates peptide hormones. Reason: The specific supported terms are angiotensin maturation (GO:0002003, a descendant via peptide hormone processing) and hormone catabolic process (GO:0042447). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12821 SUPPORTS TRANSFER Donor claim is correct and transfers to rat Ace; only the term granularity is refined. Proposed replacements: angiotensin maturation hormone catabolic process Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin UniProtKB:P47820 Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones |
| GO:0042447 hormone catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: ACE inactivates peptide hormones such as bradykinin, enkephalins and gonadoliberin. Reason: Core: inactivation of vasoactive and neuroactive peptide hormones is a defining role of ACE. Bradykinin catabolic process is not classified under this term in GO, so it is not redundant with it. Supporting Evidence: UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response UniProtKB:P47820 Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones |
| GO:0042447 hormone catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: ACE inactivates peptide hormones such as bradykinin, enkephalins and gonadoliberin. Reason: Core: inactivation of vasoactive and neuroactive peptide hormones is a defining role of ACE. Bradykinin catabolic process is not classified under this term in GO, so it is not redundant with it. Supporting Evidence: UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response UniProtKB:P47820 Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones |
| GO:0042447 hormone catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: ACE inactivates peptide hormones such as bradykinin, enkephalins and gonadoliberin. Reason: Core: inactivation of vasoactive and neuroactive peptide hormones is a defining role of ACE. Bradykinin catabolic process is not classified under this term in GO, so it is not redundant with it. Supporting Evidence: UniProtKB:P47820 Also able to inactivate bradykinin, a potent vasodilator, and therefore enhance the blood pressure response UniProtKB:P47820 Catalyzes cleavage of cholecystokinin (maturation of Cholecystokinin-8 and Cholecystokinin-5) and Gonadoliberin-1 (both maturation and degradation) hormones |
| GO:0042755 eating behavior | IMP PMID:19361967 Metabolic effects of low dose angiotensin converting enzyme ... | MARK AS OVER ANNOTATED | Summary: Low-dose perindopril reduced food intake in rats; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:19361967 Treatment with perindopril decreased food intake and circulating insulin in both diet groups |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:19301230 ACE-inhibitor suppresses the apoptosis induced by endoplasmi... | MARK AS OVER ANNOTATED | Summary: Perindopril reduced tubular apoptosis in diabetic rats; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:19301230 Increased tubular apoptosis in experimental diabetic rats is attenuated by blockade of the renin-angiotensin system with an ACE inhibitor |
| GO:0043171 peptide catabolic process | IDA PMID:16148611 N-domain angiotensin-converting enzyme isoform expression in... | ACCEPT | Summary: ACE degrades a broad set of bioactive peptides (Met-enkephalin-Arg-Phe, Ang-(1-7), AcSDKP, hemopressin) that have no specific GO catabolic terms. Reason: This term is as precise as available for the aggregate of non-hormone peptide substrates; rat ACE activity on synthetic and natural peptides was shown directly (PMID:16148611, PMID:20487892). Supporting Evidence: PMID:16148611 Two peaks (at 136 and 69 kDa) with ACE activity upon ZPhe-His-Leu were separated by gel filtration from homogenate tissues of Wistar rats PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. UniProtKB:P47820 Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) |
| GO:0043171 peptide catabolic process | ISO GO_REF:0000121 | ACCEPT | Summary: ACE degrades a broad set of bioactive peptides (Met-enkephalin-Arg-Phe, Ang-(1-7), AcSDKP, hemopressin) that have no specific GO catabolic terms. Reason: This term is as precise as available for the aggregate of non-hormone peptide substrates; rat ACE activity on synthetic and natural peptides was shown directly (PMID:16148611, PMID:20487892). Supporting Evidence: PMID:16148611 Two peaks (at 136 and 69 kDa) with ACE activity upon ZPhe-His-Leu were separated by gel filtration from homogenate tissues of Wistar rats PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. UniProtKB:P47820 Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) |
| GO:0045777 positive regulation of blood pressure | IMP PMID:17161436 Enalapril and losartan restored blood pressure and vascular ... | MODIFY | Summary: Ace raises blood pressure; refine to positive regulation of systemic arterial blood pressure. Reason: Correct but general. In PMID:17161436 enalapril normalized blood pressure in undernourished rats although ACE activity itself was unchanged; the generic claim is supported by antisense knock-down (PMID:10506486). Refined to GO:0003084. Proposed replacements: positive regulation of systemic arterial blood pressure Supporting Evidence: PMID:17161436 The treatments with losartan or enalapril normalized the blood pressure levels PMID:10506486 This was associated with a long-term reduction in blood pressure by approximately 15 mm Hg, exclusively in the spontaneously hypertensive rat. |
| GO:0045907 positive regulation of vasoconstriction | IMP PMID:17161436 Enalapril and losartan restored blood pressure and vascular ... | KEEP AS NON CORE | Summary: By generating angiotensin II and destroying bradykinin, ACE promotes vasoconstriction. Reason: A regulatory consequence of the core activity, more tissue-level than the blood-pressure terms; kept as non-core. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin PMID:17161436 The treatments with losartan or enalapril normalized the blood pressure levels |
| GO:0046325 negative regulation of D-glucose import across plasma membrane | IMP PMID:24184594 Angiotensin 1-7 improves insulin sensitivity by increasing s... | MARK AS OVER ANNOTATED | Summary: Captopril enhanced insulin-stimulated glucose uptake through Mas receptor; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:24184594 captopril (an ACE inhibitor) enhanced insulin-induced glucose uptake and this effect was blocked by the MasR antagonist A-779 |
| GO:0048167 regulation of synaptic plasticity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ACE regulates synaptic plasticity in the nucleus accumbens by cleaving Met-enkephalin-Arg-Phe (mouse donor IDA PMID:35201898). Reason: ACE performs the regulatory step (degradation of the opioid peptide). Rat synaptic membranes show the same cleavage (PMID:20487892). A real but non-core neural role. Supporting Evidence: UniProtKB:P47820 Acts as a regulator of synaptic plasticity in the nucleus accumbens of the brain by mediating cleavage of Met-enkephalin-Arg-Phe PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0048167 regulation of synaptic plasticity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ACE regulates synaptic plasticity in the nucleus accumbens by cleaving Met-enkephalin-Arg-Phe (mouse donor IDA PMID:35201898). Reason: ACE performs the regulatory step (degradation of the opioid peptide). Rat synaptic membranes show the same cleavage (PMID:20487892). A real but non-core neural role. Supporting Evidence: UniProtKB:P47820 Acts as a regulator of synaptic plasticity in the nucleus accumbens of the brain by mediating cleavage of Met-enkephalin-Arg-Phe PMID:20487892 Product release was inhibited by low concentrations of MK-421 but not by Thiorphan, indicating that the cleavage of the heptapeptide was mediated by the angiotensin converting enzyme. |
| GO:0048286 lung alveolus development | IMP PMID:22587910 Effects of maternal captopril treatment during late pregnanc... | MARK AS OVER ANNOTATED | Summary: Maternal captopril impaired neonatal alveolar formation; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:22587910 Lungs from captopril-treated animals showed impaired alveolar formation |
| GO:0050435 amyloid-beta metabolic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: The ACE N-domain degrades amyloid-beta 40/42 (by similarity to human ACE). Reason: A secondary substrate activity with uncertain physiological weight; non-core. Supporting Evidence: UniProtKB:P47820 Involved in amyloid-beta metabolism by catalyzing degradation of Amyloid-beta protein 40 and Amyloid-beta protein 42 peptides, thereby preventing plaque formation UniProtKB:P47820 Degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) and amyloid-beta proteins is mediated by the N-terminal catalytic domain, while angiotensin I and cholecystokinin cleavage is mediated by the C-terminal catalytic region |
| GO:0050482 arachidonate secretion | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Arachidonate release is a B2-receptor readout enhanced by ACE inhibitors (human donor PMID:17077303); ACE does not perform arachidonate secretion. Reason: The readout measures B2 receptor activation; ACE's role is the enzyme-receptor heterodimer that ACE inhibitors modulate. Assigning arachidonate secretion to ACE over-states its role. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P12821 SUPPORTS SOURCE BUT NOT TARGET Human donor (PMID:17077303) measured B2-receptor readouts modulated by ACE inhibitors; arachidonate release is a receptor response, not an ACE activity. Supporting Evidence: PMID:17077303 Heterodimer formation between ACE and B2 receptors can be a mechanism for ACE inhibitors to augment kinin activity at cellular level. |
| GO:0050769 positive regulation of neurogenesis | IMP PMID:20122169 Ramipril mitigates radiation-induced impairment of neurogene... | MARK AS OVER ANNOTATED | Summary: Ramipril reduced basal dentate gyrus neurogenesis; indirect. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:20122169 Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats. |
| GO:0051019 mitogen-activated protein kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: JNK co-precipitates with ACE in endothelial cells (human donor IPI PMID:14615289). Reason: Peripheral signalling-scaffold property, as for MKK7 binding. Supporting Evidence: PMID:14615289 Mitogen-activated protein kinase kinase 7 and c-Jun N-terminal kinase (JNK) coprecipitated with ACE |
| GO:0060047 heart contraction | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: From mouse cardiac ACE overexpression/knockout models (donor PMID:16585392, PMID:25017399); indirect effect via angiotensin II. Reason: ACE does not perform a step of heart contraction; the cardiac phenotypes follow from altered local angiotensin II. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin |
| GO:0060177 regulation of angiotensin metabolic process | ISO GO_REF:0000121 | MODIFY | Summary: ACE does not regulate angiotensin metabolism; it catalyses it. The correct term is angiotensin maturation. Reason: Lateral correction: the enzyme performing the conversion is annotated to the process itself. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P12821 SUPPORTS TRANSFER Donor evidence shows ACE converting angiotensin; the enzyme belongs on the process itself, not on its regulation. Proposed replacements: angiotensin maturation Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin |
| GO:0060978 angiogenesis involved in coronary vascular morphogenesis | IMP PMID:22123369 Angiotensin-converting enzyme inhibition promotes coronary a... | MARK AS OVER ANNOTATED | Summary: ACE inhibition promoted coronary capillary formation in Dahl rats; indirect and opposite in sign to involvement. Reason: This annotation rests on pharmacological ACE inhibition with a downstream physiological readout. It shows a consequence of shifting the angiotensin II / kinin balance, not a process whose steps ACE itself performs; ACE's contribution is the upstream peptide processing already captured by angiotensin maturation and bradykinin catabolic process. Supporting Evidence: PMID:22123369 ACE inhibition by perindopril promotes myocardial capillary formation |
| GO:0070062 extracellular exosome | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ACE is detected in exosome preparations (human donor); consistent with release of the membrane enzyme into body fluids. Reason: Large-scale exosome proteomics; plausible for a shed ectoenzyme, non-core. Supporting Evidence: UniProtKB:P47820 Soluble form that is released in blood plasma and other body fluids following proteolytic cleavage in the juxtamembrane stalk region. |
| GO:0070573 metallodipeptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Metallodipeptidase activity (hydrolysis of a dipeptide) does not describe ACE, which releases dipeptides from longer peptides. Reason: GO:0070573 is defined as hydrolysis of a dipeptide substrate. ACE's activity is release of a C-terminal dipeptide from an oligopeptide, captured by GO:0008241; lateral correction. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12821 SUPPORTS SOURCE BUT NOT TARGET Donor activity is ACE peptide hydrolysis; GO:0070573 is defined for dipeptide substrates, so the term mis-scopes the activity. Proposed replacements: peptidyl-dipeptidase activity Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity |
| GO:0070573 metallodipeptidase activity | ISS GO_REF:0000024 | MODIFY | Summary: Metallodipeptidase activity (hydrolysis of a dipeptide) does not describe ACE, which releases dipeptides from longer peptides. Reason: GO:0070573 is defined as hydrolysis of a dipeptide substrate. ACE's activity is release of a C-terminal dipeptide from an oligopeptide, captured by GO:0008241; lateral correction. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P12821 SUPPORTS SOURCE BUT NOT TARGET Donor activity is ACE peptide hydrolysis; GO:0070573 is defined for dipeptide substrates, so the term mis-scopes the activity. Proposed replacements: peptidyl-dipeptidase activity Supporting Evidence: UniProtKB:P47820 Dipeptidyl carboxypeptidase that removes dipeptides from the C-terminus of a variety of circulating hormones, such as angiotensin I, bradykinin or enkephalins, thereby playing a key role in the regulation of blood pressure, electrolyte homeostasis or synaptic plasticity |
| GO:0071333 cellular response to glucose stimulus | IEP PMID:17626897 Mechanism of high glucose induced angiotensin II production ... | MARK AS OVER ANNOTATED | Summary: High glucose decreases Ace expression in vascular smooth muscle cells; regulation of Ace. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:17626897 it decreased expression of angiotensin-converting enzyme (ACE), downregulated ACE-dependent Ang II generation |
| GO:0071548 response to dexamethasone | IEP PMID:1659346 [Changing factors of the activity of angiotensin converting ... | MARK AS OVER ANNOTATED | Summary: Dexamethasone lowers plasma ACE activity; regulation of Ace. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:1659346 DM elicited a significant decrease in plasma ACE activity |
| GO:0071838 cell proliferation in bone marrow | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Mouse Ace-null bone marrow phenotype (donor PMID:20116413); ACE acts by degrading AcSDKP, an inhibitor of stem-cell proliferation, not by proliferating. Reason: The regulatory role is captured by regulation of hematopoietic stem cell proliferation (GO:1902033); the process term itself over-states participation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) |
| GO:0086091 regulation of heart rate by cardiac conduction | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: From a mouse cardiac ACE overexpression model with conduction defects (donor PMID:25017399); indirect. Reason: ACE does not perform cardiac conduction; the phenotype follows from angiotensin II-driven connexin loss. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin |
| GO:0090281 negative regulation of calcium ion import | IMP PMID:10506486 Sustained inhibition of angiotensin I-converting enzyme (ACE... | MARK AS OVER ANNOTATED | Summary: ACE antisense increased AT1 receptor density and Ang II-stimulated Ca2+ rise in endothelial cells; indirect. Reason: The effect on calcium entry follows from receptor up-regulation in ACE-deficient cells, not from an activity of ACE on calcium import. Supporting Evidence: PMID:10506486 Although angiotensin II caused a concentration-dependent stimulation of intracellular Ca(2+) levels in both ACE-S- and ACE-AS-expressing cells, the stimulation was significantly higher in ACE-AS-expressing RPAECs. |
| GO:0097066 response to thyroid hormone | IEP PMID:1659346 [Changing factors of the activity of angiotensin converting ... | MARK AS OVER ANNOTATED | Summary: T3 increases renal brush-border ACE activity; regulation of Ace. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:1659346 Administering T3 produced a marked increase in the brush border ACE activity |
| GO:0097225 sperm midpiece | IDA PMID:12444051 Germinal angiotensin I-converting enzyme is totally shed fro... | KEEP AS NON CORE | Summary: Germinal ACE is on the midpiece of rat testicular sperm before being shed in the epididymis. Reason: Direct immunolocalization (PMID:12444051); location of the testis isoform, peripheral to the somatic enzyme's function. Supporting Evidence: PMID:12444051 this enzyme is immunolocalized mainly on the middle piece of rat and mouse testicular sperm PMID:12444051 the rodent germinal ACE is released from the testicular sperm membrane when sperm enter the epididymis |
| GO:1901363 heterocyclic compound binding | IDA PMID:7620708 Role of angiotensin converting enzyme in the vascular effect... | MARK AS OVER ANNOTATED | Summary: Binding of the synthetic inhibitor cFP (and a lisinopril derivative) to rat ACE is a pharmacological property, annotated to an uninformative grouping term. Reason: The cited experiment is radioligand displacement by synthetic inhibitors (PMID:7620708, abstract only in the cache). The binding is real and the inhibitors are heterocyclic, so the term is true, but 'heterocyclic compound binding' is a high-level chemical grouping class with no functional content, and drug binding to the active site is not a biological function of the gene product; the relevant activity (GO:0008241) is accepted. Marked over-annotated, as for the other inhibitor-pharmacology rows here. Supporting Evidence: PMID:7620708 CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE |
| GO:1902033 regulation of hematopoietic stem cell proliferation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ACE degrades AcSDKP, a negative regulator of hematopoietic stem cell proliferation, so ACE promotes stem-cell cycling (mouse donor PMID:20116413). Reason: ACE performs the regulatory step (peptide degradation); non-core. Supporting Evidence: UniProtKB:P47820 Also acts as a regulator of hematopoietic stem cell differentiation by mediating degradation of hemoregulatory peptide N-acetyl-SDKP (AcSDKP) |
| GO:1903522 regulation of blood circulation | IEA GO_REF:0000117 | MODIFY | Summary: ARBA-predicted regulation of blood circulation; ACE's established role is renin-angiotensin regulation of systemic arterial blood pressure. Reason: Electronic rule-based term; GO:0003081 is the accurate statement (regulation of blood pressure is not classified under regulation of blood circulation, so this is a lateral refinement). Proposed replacements: regulation of systemic arterial blood pressure by renin-angiotensin Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin |
| GO:1903597 negative regulation of gap junction assembly | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: From a mouse cardiac ACE overexpression model with reduced connexin gap junctions (donor PMID:25017399); indirect. Reason: ACE does not act on gap junction assembly; connexin loss follows from excess cardiac angiotensin II. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:87874 SOURCE WEAK OR INFERRED Donor annotation rests on a knockout/overexpression phenotype downstream of angiotensin II; it records necessity or consequence, not a step performed by ACE. Supporting Evidence: UniProtKB:P47820 Plays a major role in the angiotensin-renin system that regulates blood pressure and sodium retention by the kidney by converting angiotensin I to angiotensin II, resulting in an increase of the vasoconstrictor activity of angiotensin |
| GO:1904045 cellular response to aldosterone | IEP PMID:11447075 Aldosterone induces angiotensin-converting-enzyme gene expre... | MARK AS OVER ANNOTATED | Summary: Aldosterone induces Ace mRNA in neonatal cardiocytes; regulation of Ace. Reason: Inducible expression or activity of Ace under this condition shows that Ace is regulated by the stimulus, not that Ace executes a response to it. Expression evidence alone does not show participation in the response process. Supporting Evidence: PMID:11447075 Aldosterone upregulates ACE mRNA expression, which is blocked by spironolactone in neonatal rat cardiocytes. |
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Download this section (compressed HTML)Q: Does rat ACE (somatic or germinal) have genuine single-residue carboxypeptidase activity on any physiological substrate, as implied by the mouse metallocarboxypeptidase annotations, or do these reflect dipeptidyl trimming of antigenic peptides?
Q: Is the chromosome 10 malignant-hypertension modifier effect in Ren2 rats due to Ace expression level (and tissue AcSDKP) rather than the L341F N-domain substitution, and which tissue pool of ACE matters?
Q: GO has no specific process terms for AcSDKP or angiotensin-(1-7) degradation; should these ACE N-domain/C-domain roles be represented by new catabolic process terms, or by has_input on the peptidyl-dipeptidase activity in GO-CAM?
Experiment: Domain-selective inactivation (N- or C-domain HEXXH mutants) of rat Ace by genome editing, measuring plasma and tissue Ang II, bradykinin, AcSDKP and Ang-(1-7) and blood pressure, to apportion each physiological substrate to a domain in the rat.
Hypothesis: In the rat, angiotensin I conversion depends mainly on the C-domain and AcSDKP degradation on the N-domain.
Type: genetic perturbation with peptidomics
Experiment: Allele replacement of Fischer Ace with Lewis Ace (and vice versa) on the Ren2 inducible-hypertension background to test whether Ace alone accounts for the chromosome 10 end-organ-damage QTL.
Hypothesis: Ace expression level, not linked genes, is the chromosome 10 modifier of malignant hypertension severity.
Type: congenic allele replacement
Experiment: Unbiased substrate profiling of germinal (testis) ACE on epididymal fluid and sperm-surface peptides/GPI-anchored proteins to identify the substrates required for male fertility.
Hypothesis: Germinal ACE processes specific sperm-surface or epididymal peptide substrates required for fertilization competence.
Type: substrate profiling / proteomics
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