CYP11B2 encodes aldosterone synthase, a heme-dependent cytochrome P450 associated with the mitochondrial inner membrane of adrenal zona glomerulosa cells. It converts deoxycorticosterone to aldosterone through sequential 11-beta hydroxylation, corticosterone 18-hydroxylation and subsequent 18-oxidation, using oxygen and electrons supplied through the mitochondrial adrenodoxin system. Aldosterone production links this catalytic activity to sodium, potassium and water balance. CYP11B2 also accepts other corticosteroid substrates, including demonstrated conversion of 11-deoxycortisol to cortisol and further metabolism of cortisol to 18-oxygenated derivatives. Loss of CYP11B2 activity causes aldosterone synthase deficiency and salt wasting. The 503-residue precursor undergoes mitochondrial targeting and processing.
Definition: Catalysis of the reaction: 18-hydroxycorticosterone + 2 reduced adrenodoxin + O2 + 2 H+ = aldosterone + 2 oxidized adrenodoxin + 2 H2O. The C18 hydroxymethyl group is oxidized to the aldehyde group of aldosterone.
Justification: The final aldosterone-forming reaction is curated separately as RHEA:50792 and is performed by human CYP11B2. GO:0047783 instead converts corticosterone to 18-hydroxycorticosterone. Targeted current GO and OLS searches did not identify a molecular-function term for the final reaction, and the inspected Rhea record has no GO molecular-function mapping. This proposal requests precise representation of the established reaction, without assigning an invented GO identifier or inferring a gap merely from absence of an EC number. It does not require that freely supplied 18-hydroxycorticosterone be an efficient substrate in every assay; enzyme-bound intermediate handling is a separate mechanistic issue.
Parent term: oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
Mappings:
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006704 glucocorticoid biosynthetic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CYP11B2 has demonstrated glucocorticoid-producing chemistry in addition to its principal aldosterone role. Reason: Human CYP11B2 forms the glucocorticoid corticosterone during aldosterone synthesis and also directly converts 11-deoxycortisol to cortisol in human expression and purified-enzyme experiments (PMID:1741400 Table 1; PMID:23322723 Table 1 and Results). This broad process assertion is retained as secondary biology, without equating that biochemical range with the predominant physiological cortisol-producing role of CYP11B1. The genuine PTN001547321 node lies on the human path, and no target-specific loss of this chemistry is established. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN001547321 SUPPORTS TRANSFER Exact current IBD is on the reconstructed CYP11B2 path; seed and current descendant evidence sets remain distinct. |
| GO:0034650 cortisol metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CYP11B2 also metabolizes cortisol to 18-oxygenated derivatives. Reason: The current term includes reactions involving cortisol, not only its biosynthesis. The CYP11B2-transfected V79-cell experiments in PMID:15356073 directly converted cortisol to 18-hydroxycortisol and 18-oxo-cortisol. This secondary substrate chemistry supports the existing metabolic assertion while aldosterone synthesis remains the principal function. The genuine ancestral node lies on the CYP11B2 path; the preserved seed and current IBD donor sets differ and remain separately documented. The official P19099 reaction record independently distinguishes cortisol 18-hydroxylation (RHEA:76019) and subsequent 18-hydroxycortisol oxidation (RHEA:76023). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN001547321 SUPPORTS TRANSFER Exact current IBD is on the reconstructed CYP11B2 path; seed and current descendant evidence sets remain distinct. Supporting Evidence: GO_REF:0000033 PMID:15356073 Cortisol was converted to 18-hydroxycortisol (c4.3%) and to 18-oxo-cortisol (c1.1%) file:human/CYP11B2/CYP11B2-uniprot.txt |
| GO:0004507 steroid 11-beta-monooxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Human CYP11B2 directly catalyzes steroid 11-beta-hydroxylation. Reason: Human CYP11B2 directly catalyzes steroid 11-beta-hydroxylation in the expressed-enzyme experiments of PMID:1741400 and purified-enzyme assays of PMID:23322723. Both deoxycorticosterone and 11-deoxycortisol are substrates. The exact current IBD lies on the reconstructed target lineage, with no target-path loss record; the target's experimental descendant evidence is legitimate support. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001547324 SUPPORTS TRANSFER Exact current IBD is on the reconstructed CYP11B2 path; seed and current descendant evidence sets remain distinct. |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: CYP11B2 is catalytically active at the mitochondrial inner membrane. Reason: The current PTN001547321 IBD is on the reconstructed human lineage, with no target-path loss record. The inner-membrane location is independently supported by the human sequence record and the individually traced Reactome reaction entities. The original is_active_in qualifier is retained. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001547321 SUPPORTS TRANSFER Exact current IBD is on the reconstructed CYP11B2 path; seed and current descendant evidence sets remain distinct. Supporting Evidence: GO_REF:0000033 file:human/CYP11B2/CYP11B2-uniprot.txt Reactome:R-HSA-194017 |
| GO:0032342 aldosterone biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Inherited aldosterone synthesis is independently established for human CYP11B2. Reason: The aldosterone IBD at PTN001547324 lies on the human CYP11B2 path and has genuine experimental descendant records, including the target itself. Human CYP11B2 performs the terminal oxidation sequence that produces aldosterone. The target's own experimental evidence in the donor set is expected evidence for the ancestral inference, not circularity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001547324 SUPPORTS TRANSFER Exact current IBD is on the reconstructed CYP11B2 path; seed and current descendant evidence sets remain distinct. |
| GO:0071375 cellular response to peptide hormone stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Peptide-hormone responsiveness is a contextual regulatory property of CYP11B2 expression. Reason: The genuine PTN001547321 inference is consistent with the angiotensin-II-dependent CYP11B2 transcription measured in human H295R cells in PMID:19342457. Expression changes fit the response term; they do not make CYP11B2 a peptide-hormone receptor. Retain this contextual response separately from the enzyme's performed steroid chemistry. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN001547321 SUPPORTS TRANSFER Exact current IBD is on the reconstructed CYP11B2 path; seed and current descendant evidence sets remain distinct. |
| GO:0008203 cholesterol metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain broad cholesterol-metabolic pathway membership for the downstream steroidogenic reactions. Reason: GO:0008203 names reactions and pathways involving cholesterol, rather than requiring every participant to bind cholesterol. The actual PTN001547321 duplication node contains the CYP11A1 and CYP11B branches and lies on the reconstructed CYP11B2 path; its literal IBD is supported by CYP11A1 descendant evidence. CYP11B2 performs downstream oxidative steps in the cholesterol-derived steroid pathway explicitly represented in Reactome R-HSA-211976. It does not catalyze cholesterol side-chain cleavage. Complete current comparator queries find this term absent from CYP17A1, CYP21A2 and CYP19A1, and aldosterone biosynthesis is not a descendant of cholesterol metabolism in the inspected ontology. These findings expose a pathway-boundary convention to resolve, but neither establishes a misplaced ancestral node or loss of the broad pathway role. Retain this existing assertion conservatively as non-core, without claiming cholesterol binding, homeostatic control or direct cholesterol turnover. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN001547321 SUPPORTS TRANSFER The exact cholesterol IBD at PTN001547321 is on the CYP11B2 path and cites CYP11A1 descendants. This is a family-tree ancestral judgment, not a pairwise CYP11A1-to-CYP11B2 ortholog transfer. No target-path IRD/IKR loss record was found; broad pathway scope, rather than cholesterol substrate recognition, is retained. Supporting Evidence: GO_REF:0000033 Reactome:R-HSA-211976 Reactome:R-HSA-193993 |
| GO:0047783 corticosterone 18-monooxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: CYP11B2 directly hydroxylates corticosterone at C18. Reason: Human CYP11B2 directly hydroxylates corticosterone at C18. GO:0047783 and RHEA:11872 describe this corticosterone-to-18-hydroxycorticosterone reaction, not the subsequent oxidation to aldosterone. The exact current IBD is on the reconstructed human path and agrees with the independent human enzyme evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001547324 SUPPORTS TRANSFER Exact current IBD is on the reconstructed CYP11B2 path; seed and current descendant evidence sets remain distinct. |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000002 | MODIFY | Summary: Refine the broad monooxygenase class to the two demonstrated steroid activities. Reason: The P450 monooxygenase classification is valid, but human CYP11B2 has experimentally established steroid 11-beta-hydroxylation and corticosterone 18-hydroxylation activities. These two specific existing functions refine the broad domain-based assertion without implying that generic P450 signatures alone determine regioselectivity. The final aldosterone-forming 18-oxidation remains distinct from the definition of GO:0047783. The replacement term or terms are already represented by separate existing assertions; this refines this source tuple and does not propose a NEW annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR001128 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR002399 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR036396 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. Proposed replacements: steroid 11-beta-monooxygenase activity corticosterone 18-monooxygenase activity Supporting Evidence: GO_REF:0000002 PMID:1741400 exhibits steroid 11 beta-hydroxylase activity as well. |
| GO:0004507 steroid 11-beta-monooxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic sources identify an experimentally established steroid 11-beta oxidation. Reason: The current ARBA00029264 branch requires the three recorded P450 features and excludes Insecta; CYP11B2 satisfies it. The original EC and Rhea identifiers are preserved. Independent human biochemical work establishes 11-beta hydroxylation of deoxycorticosterone, so this is a supported catalytic assignment rather than an inference from a P450 name alone. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00029264 SUPPORTS TRANSFER Complete current rule predicates were evaluated against official CYP11B2 features and taxonomy; a matching branch is present. RHEA:15629 SUPPORTS TRANSFER Literal catalytic source retained; the reaction class agrees with independent human enzyme evidence. RHEA:46100 SUPPORTS TRANSFER Literal catalytic source retained; the reaction class agrees with independent human enzyme evidence. RHEA:46104 SUPPORTS TRANSFER Literal catalytic source retained; the reaction class agrees with independent human enzyme evidence. RHEA:84067 SUPPORTS TRANSFER Literal catalytic source retained; the reaction class agrees with independent human enzyme evidence. EC:1.14.15.4 SUPPORTS TRANSFER Literal catalytic source retained; the reaction class agrees with independent human enzyme evidence. |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: CYP11B2 coordinates the iron of its catalytic heme. Reason: The four literal InterPro sources all carry the iron-binding mapping and are present in the official CYP11B2 record. The human structure and the annotated axial heme ligand support iron coordination as a property of the P450 active site. This is cofactor binding, not a separate iron-transport function. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001128 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR002399 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR017972 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR036396 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: CYP11B2 has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: The earlier rule/source audit found a matching ARBA00026962 branch and InterPro IPR002399 mapping. Preserve those source identities while accepting the mitochondrial claim on independently curated target localization; matching electronic predictions are not experimental topology evidence. Organelle granularity is not a propagation failure. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026962 SUPPORTS TRANSFER Complete current rule predicates were evaluated against official CYP11B2 features and taxonomy; a matching branch is present. The matching provenance is retained; the supported root-organelle claim needs no granularity correction and is independently corroborated by curated target localization. InterPro:IPR002399 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. The matching provenance is retained; the supported root-organelle claim needs no granularity correction and is independently corroborated by curated target localization. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt location mapping correctly places CYP11B2 at the mitochondrial inner membrane. Reason: SL-0168 maps to the same inner-membrane location recorded for CYP11B2. The processed chain and the reaction-model protein entity are consistent with this localization. Preserve the located_in qualifier; this record does not itself establish membrane topology or a distinct transmembrane segment. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0168 SUPPORTS TRANSFER Literal source is retained and assessed with independent target evidence as described in the reason. Supporting Evidence: GO_REF:0000044 file:human/CYP11B2/CYP11B2-uniprot.txt |
| GO:0016125 sterol metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The matching electronic sterol-pathway assignment is broad but compatible with CYP11B2 chemistry. Reason: ARBA00034378 branch 8 matches the official CYP11B2 features and taxonomy. The term includes sterol-related pathways, and CYP11B2 performs the downstream aldosterone-producing reactions in the cholesterol-derived steroid-hormone pathway. Retain this broad context without claiming direct cholesterol turnover or sterol-homeostatic regulation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00034378 SUPPORTS TRANSFER Complete current rule predicates were evaluated against official CYP11B2 features and taxonomy; a matching branch is present. Supporting Evidence: GO_REF:0000117 Reactome:R-HSA-211976 |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000002 | MODIFY | Summary: Refine the broad paired-donor oxidoreductase class to the demonstrated steroid activities. Reason: The broad paired-donor oxidoreductase class is correct. Direct assays of purified human CYP11B2 with human adrenodoxin and adrenodoxin reductase establish the two more informative steroid monooxygenase activities. These refinements are supported by the actual enzyme assays rather than being inferred solely from an InterPro domain. Neither specific term is an ancestor of the other in the saved current ontology. The replacement term or terms are already represented by separate existing assertions; this refines this source tuple and does not propose a NEW annotation. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR001128 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR002399 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR017972 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR036396 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. Proposed replacements: steroid 11-beta-monooxygenase activity corticosterone 18-monooxygenase activity Supporting Evidence: GO_REF:0000002 PMID:23322723 high 11Ξ²-hydroxylase activity of aldosterone synthase |
| GO:0020037 heme binding | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic heme-binding annotation matches CYP11B2's catalytic prosthetic group. Reason: The current ARBA00026797 branch 1 matches the recorded FunFam and primate lineage, and the literal InterPro mappings support heme binding. Human structural evidence independently establishes the bound heme. This cofactor property belongs to the steroid-oxidation machinery and does not require a separate core activity unit. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026797 SUPPORTS TRANSFER Complete current rule predicates were evaluated against official CYP11B2 features and taxonomy; a matching branch is present. InterPro:IPR001128 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR002399 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. InterPro:IPR036396 SUPPORTS TRANSFER The literal InterPro record and GO mapping were inspected and match the official target features. |
| GO:0032342 aldosterone biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: The matching aldosterone rule agrees with direct CYP11B2 chemistry. Reason: ARBA00095220 branch 0 requires three present P450 features and excludes Schizosaccharomyces; CYP11B2 satisfies those predicates. Direct human expression and biochemical studies establish aldosterone production, independently supporting the rule conclusion rather than relying on domain membership alone. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00095220 SUPPORTS TRANSFER Complete current rule predicates were evaluated against official CYP11B2 features and taxonomy; a matching branch is present. |
| GO:0047783 corticosterone 18-monooxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The literal Rhea and EC sources identify corticosterone 18-hydroxylation. Reason: The literal source RHEA:11872 and EC:1.14.15.5 correspond to corticosterone 18-hydroxylation, matching GO:0047783 and positive human enzyme assays. RHEA:50792 separately represents the subsequent 18-hydroxycorticosterone-to-aldosterone oxidation; that final step is not conflated with the term's defined reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:11872 SUPPORTS TRANSFER Literal catalytic source retained; the reaction class agrees with independent human enzyme evidence. EC:1.14.15.5 SUPPORTS TRANSFER Literal catalytic source retained; the reaction class agrees with independent human enzyme evidence. |
| GO:0006705 mineralocorticoid biosynthetic process | TAS Reactome:R-HSA-193993 | MODIFY | Summary: Specify aldosterone synthesis within the broader mineralocorticoid pathway. Reason: Reactome R-HSA-193993 explicitly identifies CYP11B2 as the catalyst of the three reactions from deoxycorticosterone to aldosterone. Aldosterone biosynthetic process captures this performed output more precisely than the parent mineralocorticoid term. Existing independent aldosterone rows remain separate source tuples. Proposed replacements: aldosterone biosynthetic process Supporting Evidence: Reactome:R-HSA-193993 converted to aldosterone in a three-reaction sequence catalyzed by CYP11B2 |
| GO:0016125 sterol metabolic process | TAS Reactome:R-HSA-211976 | KEEP AS NON CORE | Summary: The broad Reactome cholesterol-metabolic annotation reflects performed downstream steroid synthesis. Reason: R-HSA-211976 explicitly includes steroid-hormone synthesis among cholesterol-elimination pathways and contains the CYP11B2 catalytic reactions through mineralocorticoid biosynthesis. This supports pathway membership rather than direct cholesterol binding, cholesterol side-chain cleavage, or control of cholesterol homeostasis. Supporting Evidence: Reactome:R-HSA-211976 Reactome:R-HSA-193993 |
| GO:0004507 steroid 11-beta-monooxygenase activity | TAS Reactome:R-HSA-194017 | ACCEPT | Summary: The normal Reactome event assigns the correct first oxidation to CYP11B2. Reason: R-HSA-194017 consumes deoxycorticosterone and produces corticosterone through catalyst 5600617, GO:0004507, and the human CYP11B2 entity 194019/P19099. This is the experimentally established 11-beta hydroxylation step of aldosterone synthesis. |
| GO:0004507 steroid 11-beta-monooxygenase activity | TAS Reactome:R-HSA-5600598 | ACCEPT | Summary: Steroid 11-beta oxidation is a real wild-type CYP11B2 function despite this disease-model citation. Reason: The cited FailedReaction models loss of the normal deoxycorticosterone oxidation in a set of CYP11B2 disease variants. It links explicitly to normal reaction R-HSA-194017. Retain the correct gene-level activity on independent wild-type human enzyme evidence; the mutant set is not treated as a successful catalytic assay or evidence that every listed variant retains activity. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Retain inner-membrane localization while correcting the donor's identity in the interpretation. Reason: The literal donor P14137 is rat Cyp11a1, a mitochondrial P450 paralog, not a bovine CYP11B ortholog. Its current experimental inner-membrane records are genuine. Conserved localization is also supported independently for human CYP11B2 by its sequence annotation and normal reaction entities, so the target compartment is retained without rewriting the original WITH/FROM or presenting this donor as an ortholog. The propagation flags identify this ortholog-transfer method mismatch, not a defect in the rat source annotation or a negative localization claim for human CYP11B2. The official identity is directly checkable at https://www.uniprot.org/uniprotkb/P14137/entry (Rattus norvegicus Cyp11a1). Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG Sources checked: UniProtKB:P14137 SUPPORTS SOURCE BUT NOT TARGET Rat Cyp11a1 has genuine experimental mitochondrial inner-membrane evidence, but it is a paralog rather than a CYP11B2 ortholog. The mismatch concerns the declared ortholog-transfer premise; independently supported human CYP11B2 localization remains positive. Supporting Evidence: GO_REF:0000024 file:human/CYP11B2/CYP11B2-uniprot.txt Reactome:R-HSA-194017 |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: CYP11B2 has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: The prior source audit and committed source-access guide identify P19099/CYP11B2 as MitoCoP NotID_130, included through literature pool 4 with experimental identification fields empty. Retain supported mitochondrial membership without claiming direct mass-spectrometry detection. This follow-up read that source guide and the curated target location; it does not claim a new workbook or original-image inspection. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-5600598 | ACCEPT | Summary: The failed 11-beta-oxidation model locates its CYP11B2 mutant set at the inner membrane. Reason: R-HSA-5600598 links catalyst 9631752 to mutant set 5600661 and its individual P19099-derived members, each assigned the mitochondrial inner membrane. This agrees with the independently established gene-level location. The model annotation is not an independent localization experiment for every mutant. Supporting Evidence: Reactome:R-HSA-5600598 file:human/CYP11B2/CYP11B2-uniprot.txt |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6785244 | ACCEPT | Summary: The failed terminal-oxidation model retains the correct CYP11B2 compartment. Reason: R-HSA-6785244 links its catalytic role to the inner-membrane CYP11B2 mutant set and points to the normal 18-hydroxycorticosterone-to-aldosterone reaction. Preserve the compartment annotation while separating the database's modeled location from a direct mutant localization assay. Supporting Evidence: Reactome:R-HSA-6785244 Reactome:R-HSA-193965 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6785245 | ACCEPT | Summary: The failed corticosterone-hydroxylation model uses the correct inner-membrane compartment. Reason: R-HSA-6785245 traces through catalyst 9631777 to the same P19099-derived mutant set at the mitochondrial inner membrane. Normal human CYP11B2 localization independently supports this gene-level assertion; the disease model does not demonstrate successful catalysis or localization measurements for each variant. Supporting Evidence: Reactome:R-HSA-6785245 Reactome:R-HSA-193995 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-193965 | ACCEPT | Summary: CYP11B2 carries out terminal aldosterone oxidation at the mitochondrial inner membrane. Reason: The normal R-HSA-193965 reaction traces through catalyst 193967 to CYP11B2 entity 194019, the processed 25β503 chain of P19099 assigned the inner membrane. Its matrix-localized steroid inputs and products are distinct from the enzyme's membrane association. Supporting Evidence: Reactome:R-HSA-193965 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-193995 | ACCEPT | Summary: The corticosterone 18-hydroxylation event places CYP11B2 at the inner membrane. Reason: R-HSA-193995 directly connects its catalytic role to human CYP11B2 entity 194019 at the mitochondrial inner membrane. The matrix compartment assigned to reaction metabolites does not relocate the membrane-associated enzyme. Supporting Evidence: Reactome:R-HSA-193995 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-194017 | ACCEPT | Summary: The deoxycorticosterone oxidation event places CYP11B2 at the inner membrane. Reason: R-HSA-194017 identifies catalyst 5600617 and the P19099-derived processed chain 194019 at the mitochondrial inner membrane. This is consistent with the enzyme's mitochondrial targeting and established steroidogenic location. Supporting Evidence: Reactome:R-HSA-194017 |
| GO:0008395 steroid hydroxylase activity | TAS Reactome:R-HSA-193965 | MODIFY | Summary: Refine the gene-level steroid-hydroxylase assertion to its supported specific activities. Reason: R-HSA-193965 models 18-hydroxycorticosterone oxidation to aldosterone and uses the shared steroid-hydroxylase catalyst entity 193967. CYP11B2 genuinely performs steroid hydroxylations, but this event is the later 18-oxidation step. GO:0047783 specifically names corticosterone-to-18-hydroxycorticosterone conversion and should not be substituted as if it described this final reaction. ACCEPT retains the independently established gene-level steroid-hydroxylase property, not an exact reaction mapping for this terminal oxidation. The specific final 18-oxidation is represented separately by the proposed molecular-function term and RHEA:50792; GO:0047783 is appropriate only for the preceding hydroxylation sources. At the gene-claim level, refine this broad term consistently to steroid 11-beta-monooxygenase and corticosterone 18-monooxygenase activity. Neither replacement is asserted to describe the terminal 18-oxidation reaction, which remains separately represented by the proposed molecular function. Proposed replacements: steroid 11-beta-monooxygenase activity corticosterone 18-monooxygenase activity |
| GO:0008395 steroid hydroxylase activity | TAS Reactome:R-HSA-193995 | MODIFY | Summary: Refine the gene-level steroid-hydroxylase assertion to its supported specific activities. Reason: R-HSA-193995 specifically consumes corticosterone and produces 18-hydroxycorticosterone through human CYP11B2. GO:0047783 names that reaction more precisely than the broad steroid-hydroxylase assignment. It does not by itself describe the subsequent oxidation to aldosterone. The replacement term or terms are already represented by separate existing assertions; this refines this source tuple and does not propose a NEW annotation. At the gene-claim level, refine this broad term consistently to steroid 11-beta-monooxygenase and corticosterone 18-monooxygenase activity. Neither replacement is asserted to describe the terminal 18-oxidation reaction, which remains separately represented by the proposed molecular function. Proposed replacements: steroid 11-beta-monooxygenase activity corticosterone 18-monooxygenase activity Supporting Evidence: Reactome:R-HSA-193995 Corticosterone, NADPH + H+, and O2 react to form 18-hydroxycorticosterone |
| GO:0008395 steroid hydroxylase activity | TAS Reactome:R-HSA-6785244 | MODIFY | Summary: Refine the gene-level steroid-hydroxylase assertion to its supported specific activities. Reason: R-HSA-6785244 represents defective 18-hydroxycorticosterone oxidation by a CYP11B2 mutant set and links to the corresponding normal event. The gene-level steroid-hydroxylase property is independently established, but this source does not show successful catalysis by the variants. The final oxidation is not relabeled as the earlier corticosterone 18-monooxygenase reaction. ACCEPT retains the independently established gene-level steroid-hydroxylase property, not an exact reaction mapping for this terminal oxidation. The specific final 18-oxidation is represented separately by the proposed molecular-function term and RHEA:50792; GO:0047783 is appropriate only for the preceding hydroxylation sources. At the gene-claim level, refine this broad term consistently to steroid 11-beta-monooxygenase and corticosterone 18-monooxygenase activity. Neither replacement is asserted to describe the terminal 18-oxidation reaction, which remains separately represented by the proposed molecular function. Proposed replacements: steroid 11-beta-monooxygenase activity corticosterone 18-monooxygenase activity Supporting Evidence: Reactome:R-HSA-6785244 Reactome:R-HSA-193965 |
| GO:0008395 steroid hydroxylase activity | TAS Reactome:R-HSA-6785245 | MODIFY | Summary: Refine the gene-level steroid-hydroxylase assertion to its supported specific activities. Reason: R-HSA-6785245 represents failure of the normal corticosterone-to-18-hydroxycorticosterone reaction, R-HSA-193995. GO:0047783 is the exact wild-type activity affected. The refinement applies to the established human gene function and does not claim that every member of the modeled disease set successfully catalyzes it. The replacement term or terms are already represented by separate existing assertions; this refines this source tuple and does not propose a NEW annotation. At the gene-claim level, refine this broad term consistently to steroid 11-beta-monooxygenase and corticosterone 18-monooxygenase activity. Neither replacement is asserted to describe the terminal 18-oxidation reaction, which remains separately represented by the proposed molecular function. Proposed replacements: steroid 11-beta-monooxygenase activity corticosterone 18-monooxygenase activity Supporting Evidence: Reactome:R-HSA-6785245 Reactome:R-HSA-193995 form 18-hydroxycorticosterone |
| GO:0004507 steroid 11-beta-monooxygenase activity | IDA PMID:23322723 Structural insights into aldosterone synthase substrate spec... | ACCEPT | Summary: Purified human CYP11B2 has directly measured steroid 11-beta-monooxygenase activity. Reason: The original study directly measures 11-beta-hydroxylation by purified human CYP11B2 with human electron-transfer partners, including deoxycorticosterone and 11-deoxycortisol substrates. Its crystallography identifies the substrate/heme arrangement. The tested protein was an engineered N-terminally shortened, C-terminally His-tagged construct expressed in E. coli; it must not be described as an assay of an intact native precursor or a separate physiological splice product. Supporting Evidence: |
| GO:0020037 heme binding | IDA PMID:23322723 Structural insights into aldosterone synthase substrate spec... | ACCEPT | Summary: Heme is directly observed in the human CYP11B2 structures. Reason: The original CYP11B2 structures directly contain heme; the official sequence maps the axial heme-binding cysteine to residue 450. This is a positive catalytic-cofactor binding assertion. This cofactor supports the steroid-oxidation machinery; crystallographic multiplicity does not establish native oligomer stoichiometry. Supporting Evidence: |
| GO:0032342 aldosterone biosynthetic process | IDA PMID:23322723 Structural insights into aldosterone synthase substrate spec... | ACCEPT | Summary: Reconstituted human CYP11B2 directly produces aldosterone. Reason: The original human CYP11B2 reconstitution directly produces aldosterone from deoxycorticosterone. CYP11B2 performs the oxidative chemistry rather than merely being necessary for an endocrine phenotype. The time course releases corticosterone and 18-hydroxycorticosterone intermediates, so the process must not be described as universally processive with no intermediate release. Supporting Evidence: |
| GO:0035865 cellular response to potassium ion | IEP PMID:19342457 Regulation of aldosterone and cortisol production by the tra... | KEEP AS NON CORE | Summary: Potassium stimulation changes CYP11B2 expression in the cited adrenal-cell experiments. Reason: The original human H295R experiments measure CYP11B2 mRNA induction after potassium treatment and its modulation by dominant-negative NRSF. Such expression changes fit the response term. Retain the existing IEP annotation as a regulatory context; it does not identify CYP11B2 as a potassium channel or sensor. Supporting Evidence: |
| GO:0032342 aldosterone biosynthetic process | IMP PMID:19342457 Regulation of aldosterone and cortisol production by the tra... | ACCEPT | Summary: CYP11B2 performs aldosterone synthesis within the regulated adrenal-cell pathway. Reason: The cited NRSF perturbation increases CYP11B2 transcription and aldosterone secretion in H295R cells, but does not isolate CYP11B2 by a gene-specific intervention. Its performed aldosterone-producing role is independently established by human enzyme-expression studies. Preserve the positive IMP source with this distinction between pathway regulation and direct enzyme evidence. |
| GO:0032870 cellular response to hormone stimulus | IEP PMID:19342457 Regulation of aldosterone and cortisol production by the tra... | MODIFY | Summary: Specify the demonstrated cellular response to the peptide hormone angiotensin II. Reason: The source measures angiotensin-II-stimulated CYP11B2 transcription in human H295R cells and the effect of dominant-negative NRSF on that response. Cellular response to peptide hormone stimulus captures the tested context more precisely than response to hormone. This expression-based response does not imply receptor activity by CYP11B2. Proposed replacements: cellular response to peptide hormone stimulus Supporting Evidence: PMID:19342457 angiotensin II- and K(+)-stimulated augmentation of CYP11B2 and CYP11B1 gene transcription. |
| GO:0034651 cortisol biosynthetic process | IMP PMID:19342457 Regulation of aldosterone and cortisol production by the tra... | KEEP AS NON CORE | Summary: Retain demonstrated CYP11B2 cortisol-forming chemistry as a secondary activity, with the cited regulatory experiment kept distinct. Reason: The cited NRSF study changes CYP11B1 and CYP11B2 expression and steroid secretion together; its human H295R experiment does not isolate a CYP11B2-specific cortisol-producing step. Independent wild-type human CYP11B2 expression assays directly form cortisol from 11-deoxycortisol (PMID:1741400 Table 1), and purified human CYP11B2 with human Adx/AdR confirms that turnover (PMID:23322723 Table 1 and Results). The official enzyme record maps this reaction to RHEA:46100. GO:0034651 is not limited to the predominant physiological adrenal route. Retain the existing positive assertion as contextual biochemical activity while preserving the original IMP source and its limitation; this does not assign CYP11B2 the principal physiological cortisol-producing role or resolve the separate patient-source NOT assertion. Supporting Evidence: PMID:19342457 increased human CYP11B2 and CYP11B1 mRNA expression file:human/CYP11B2/CYP11B2-uniprot.txt |
| GO:0034651 cortisol biosynthetic process | IMP NOT PMID:9703385 Molecular genetic study in two patients with congenital hypo... | UNDECIDED | Summary: The source-specific scope of the NOT cortisol-biosynthesis assertion remains unresolved. Reason: This is the preserved NOT cortisol-biosynthesis assertion. The complete cached abstract and recovered indexed original Results report normal cortisol/precursor levels in the aldosterone-deficient patients; the molecularly resolved family has homozygous E255X, whereas the type-II index case has only a heterozygous V386A variant with little effect on enzyme activity. These observations support physiological dispensability for maintaining cortisol levels, but do not establish that CYP11B2 never performs cortisol-forming chemistry. Independent wild-type human assays directly convert 11-deoxycortisol to cortisol (1992 Table 1 and 2013 Table 1/Results); the 2002 mutagenesis original also includes a positive wild-type comparator. GO:0034651 is not explicitly restricted to the physiologically predominant adrenal route. The complete patient original was not recovered, so retain the literal negation but leave its unconditional scope unresolved rather than reject the patient findings or manufacture a new positive cortisol annotation. |
| GO:0002017 regulation of blood volume by renal aldosterone | IMP PMID:14614232 A missense mutation (GGC[435Gly]-->AGC[Ser]) in exon 8 of th... | KEEP AS NON CORE | Summary: Aldosterone-dependent blood-volume regulation is a downstream consequence of CYP11B2 catalysis. Reason: The accessible patient-study abstract reports homozygous G435S CYP11B2 and reduced steroid 18-hydroxylase/oxidase activity in expression studies. The full clinical blood-volume endpoint was not recovered. Retain the curator's established aldosterone-mediated physiological context, while distinguishing it from CYP11B2 acting directly on renal transport or measuring blood volume in the accessed abstract. Supporting Evidence: PMID:14614232 steroid 18-hydroxylase/oxidase activities of the mutant enzyme were substantially reduced. |
| GO:0003091 renal water homeostasis | IC PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | KEEP AS NON CORE | Summary: Renal water homeostasis is a supported downstream inference from aldosterone synthesis. Reason: The original IC record explicitly uses aldosterone biosynthetic process as its supporting entity. CYP11B2 supplies the hormone whose renal effects influence water balance; it is not itself a renal transporter. Preserve this broad physiological consequence as non-core, separate from the direct steroid-producing activity demonstrated by the cited expression study. Supporting Evidence: |
| GO:0004507 steroid 11-beta-monooxygenase activity | IDA PMID:1741400 Role of steroid 11 beta-hydroxylase and steroid 18-hydroxyla... | ACCEPT | Summary: Expressed human CYP11B2 directly hydroxylates the tested steroids at C11. Reason: The complete original expressed human full coding-region CYP11B2 in COS7 cells, isolated mitochondrial fractions, and measured steroid products by HPLC. Table 1 directly demonstrates both deoxycorticosterone-to-corticosterone and 11-deoxycortisol-to-cortisol conversion. COS7 is the heterologous host, not a human cell line; the source does not require a mutant-only interpretation. Supporting Evidence: |
| GO:0004507 steroid 11-beta-monooxygenase activity | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: The positive source abstract and independent human assays support 11-beta hydroxylation. Reason: The complete source abstract explicitly identifies a 503-residue human adrenal-tumor cDNA and reports corticosterone formation from deoxycorticosterone after COS7 expression. The full original remains inaccessible; retain the positive curated IDA with this access limit and independent direct corroboration from the recovered 1992 and 2013 originals, without inventing details of the 1990 assay. |
| GO:0005739 mitochondrion | IDA PMID:1741400 Role of steroid 11 beta-hydroxylase and steroid 18-hydroxyla... | ACCEPT | Summary: CYP11B2 has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: The original curated direct-assay mitochondrial annotation is consistent with the target location. The prior source guide records mitochondrial fractionation, marker controls and immunoblot of expressed CYP11B2 in the 1992 original. This follow-up preserves that access account; the normal cache remains abstract-only, so no new full-text inspection or independent membrane-topology result is claimed. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IC PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: Retain the inferred inner-membrane location with its source-specific experimental limit. Reason: Retain the curator's IC localization at the mitochondrial inner membrane. The official human record annotates peripheral inner-membrane association by similarity to P14137, while the recovered human expression study directly supports the broader mitochondrial compartment. The exact 1990 full-text localization assay remains unread; distinguish the inference from direct human membrane-topology evidence. |
| GO:0006700 C21-steroid hormone biosynthetic process | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | MODIFY | Summary: Refine the broad C21-steroid claim to aldosterone biosynthesis and the separately supported secondary cortisol-forming activity. Reason: PMID:2256920 demonstrates the aldosterone-producing sequence. Independent human CYP11B2 assays also form cortisol from 11-deoxycortisol (PMID:1741400 Table 1; PMID:23322723 Table 1 and Results), retained as secondary chemistry in the existing GO:0034651 row. Replace the broad claim with both supported specific product pathways, GO:0032342 and GO:0034651, instead of repeating the glucocorticoid ancestor GO:0006704. This preserves all supported descendant coverage without claiming cortisol is the principal physiological output or resolving the separate patient-source NOT assertion. Proposed replacements: aldosterone biosynthetic process cortisol biosynthetic process Supporting Evidence: PMID:2256920 conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone |
| GO:0020037 heme binding | IC PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: Heme binding is supported as a catalytic-cofactor property. Reason: The IC heme-binding inference is consistent with the actual cytochrome P450 chemistry and is independently confirmed by the later human CYP11B2 crystal structures and axial Cys450 annotation. Retain it as an enabling cofactor property; do not recast the original IC as a directly inspected 1990 structural experiment. |
| GO:0032342 aldosterone biosynthetic process | IDA PMID:1741400 Role of steroid 11 beta-hydroxylase and steroid 18-hydroxyla... | ACCEPT | Summary: The original human expression study directly demonstrates aldosterone production. Reason: The complete 1992 original Table 1 and chromatographic Results directly demonstrate aldosterone production by expressed human CYP11B2 from deoxycorticosterone and corticosterone. The gene product performs the sequential oxidative steps. This positive aldosterone role does not require denying the same table's measured cortisol-forming side activity. Supporting Evidence: |
| GO:0032342 aldosterone biosynthetic process | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: Retain the directly reported aldosterone-producing role. Reason: The source abstract explicitly reports preferential conversion of deoxycorticosterone to aldosterone by human CYP11B2, compared with CYP11B1 under the tested conditions. Keep the source-specific access limit: full 1990 Methods were not recovered. The direct aldosterone chemistry is independently established in the recovered 1992 and 2013 originals. |
| GO:0055075 potassium ion homeostasis | IMP PMID:9838244 Homozygous deletion of arginine-173 in the CYP11B2 gene in a... | KEEP AS NON CORE | Summary: CYP11B2 deficiency affects potassium balance through loss of aldosterone production. Reason: The accessible case-report abstract documents elevated plasma potassium and renin, salt wasting, an abnormal 18-hydroxycorticosterone/aldosterone ratio, and a homozygous CYP11B2 codon-173 deletion. These positive human findings support the existing homeostasis annotation. The full paper was not recovered, and the historical variant is not assigned to an untested modern product sequence. Supporting Evidence: PMID:9838244 low plasma sodium and elevated potassium and renin. |
| GO:0055078 sodium ion homeostasis | IMP PMID:9838244 Homozygous deletion of arginine-173 in the CYP11B2 gene in a... | KEEP AS NON CORE | Summary: CYP11B2 deficiency affects sodium balance through its aldosterone-producing role. Reason: The cited human case-report abstract explicitly reports low plasma sodium and salt wasting with biochemical aldosterone-synthase deficiency and a homozygous CYP11B2 deletion. Retain this positive physiological association as non-core. It does not imply that CYP11B2 transports sodium, and no additional full-text clinical measurement is claimed. Supporting Evidence: PMID:9838244 Salt wasting was caused by an enzymatic defect |
| GO:0005739 mitochondrion | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: CYP11B2 has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: Retain the original curated mitochondrial annotation, corroborated by the independently supported target compartment and the prior 1992-source audit. The accessible 1990 abstract describes human cDNA expression and chemistry but does not resolve the localization methods; full 1990 methods were not recovered. This limitation does not invalidate the supported organelle claim or make it an inner-membrane assay. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
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Q: How do substrate access and intermediate release control the balance between 18-hydroxycorticosterone accumulation and completed aldosterone synthesis in native mitochondria?
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