CYP11B2 (aldosterone synthase; cytochrome P450 11B2, also called P450c11AS / P450aldo / P450C18) is a mitochondrial inner-membrane, heme-thiolate cytochrome P450 monooxygenase expressed in the zona glomerulosa of the adrenal cortex. It catalyzes the final three sequential steps of mineralocorticoid biosynthesis on a single active site: 11-beta-hydroxylation of 11-deoxycorticosterone to corticosterone, 18-hydroxylation of corticosterone to 18-hydroxycorticosterone, and 18-oxidation to yield aldosterone, the principal mineralocorticoid governing sodium/potassium and water balance. Catalysis uses molecular oxygen and NADPH- derived electrons delivered by the mitochondrial adrenodoxin/adrenodoxin-reductase (ferredoxin FDX1/FDX2 and ferredoxin reductase FDXR) electron-transfer system. CYP11B2 is more than 93% identical to the glucocorticoid-forming 11-beta- hydroxylase CYP11B1, but unlike CYP11B1 it possesses the 18-oxidase activity required to convert 18-hydroxycorticosterone to aldosterone, which functionally distinguishes the two isozymes. Loss-of-function variants cause aldosterone synthase (corticosterone methyloxidase, CMO type I and type II) deficiency, a salt-wasting disorder, whereas a CYP11B1/CYP11B2 chimeric gene arising from unequal crossover causes glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type I).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006704 glucocorticoid biosynthetic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA transfer of glucocorticoid biosynthesis across the CYP11B/CYP27 clade. In humans the physiological glucocorticoid (cortisol) producer is the paralog CYP11B1, not CYP11B2; CYP11B2 physiologically makes the mineralocorticoid aldosterone. CYP11B2 can produce cortisol from 11-deoxycortisol in vitro, but this is not its physiological role. Reason: The 93%-identical paralogs CYP11B1 and CYP11B2 have distinct physiological roles; CYP11B2 participates in mineralocorticoid (aldosterone) synthesis while CYP11B1 makes glucocorticoids. The IBA over-broadens a clade-level glucocorticoid role onto the aldosterone synthase. Kept (not removed) as it reflects a low-level in-vitro activity, but flagged as over-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Supporting Evidence: PMID:1741400 the former participates in the synthesis of glucocorticoids whereas the latter participates in the synthesis of mineralocorticoids in humans. |
| GO:0034650 cortisol metabolic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA cortisol metabolic process, transferred across the CYP11B clade. As with glucocorticoid biosynthesis, physiological cortisol handling is the role of CYP11B1; CYP11B2's physiological product is aldosterone. Reason: Cortisol metabolism is not the physiological role of CYP11B2 (that is CYP11B1). CYP11B2 can act on cortisol in vitro (producing 18-hydroxycortisol and 18-oxocortisol, elevated in primary aldosteronism), so the term is not strictly wrong, but it over-broadens a clade-level role and is not core. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Supporting Evidence: PMID:1741400 the former participates in the synthesis of glucocorticoids whereas the latter participates in the synthesis of mineralocorticoids in humans. |
| GO:0004507 steroid 11-beta-monooxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Steroid 11-beta-monooxygenase (EC 1.14.15.4) activity, transferred by phylogeny. This is a genuine core catalytic activity of CYP11B2: it 11-beta-hydroxylates 11-deoxycorticosterone to corticosterone as the first of its three sequential reactions toward aldosterone. Reason: Directly supported by biochemistry and structure of human aldosterone synthase; the IBA is at an appropriate level of specificity for this MF. Supporting Evidence: PMID:23322723 explains the high 11Ξ²-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial inner membrane localization (is_active_in), by phylogeny. CYP11B2 is a mitochondrial inner-membrane P450 that receives electrons from the matrix-facing adrenodoxin system; this is its correct site of action. Reason: Consistent with UniProt subcellular location and Reactome, which place the catalysis at the inner mitochondrial membrane. Core cellular component. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane Reactome:R-HSA-193995 This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. |
| GO:0032342 aldosterone biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Aldosterone biosynthetic process, by phylogeny. This is the defining biological role of CYP11B2 - it catalyzes the terminal reactions producing aldosterone in the adrenal zona glomerulosa. Reason: Core biological process; well supported experimentally and by the enzyme's unique 18-oxidase capability among the CYP11B isozymes. Supporting Evidence: PMID:2256920 P-450aldo preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone |
| GO:0071375 cellular response to peptide hormone stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cellular response to peptide hormone stimulus, by phylogeny. CYP11B2 transcription is induced by angiotensin II (a peptide hormone), consistent with regulation of aldosterone output by the renin-angiotensin system. Reason: Reflects transcriptional regulation of the gene by angiotensin II rather than a molecular function of the protein; a real but peripheral/regulatory process, not the enzyme's core function. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Expression is induced by angiotensin II |
| GO:0008203 cholesterol metabolic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Cholesterol metabolic process, transferred across the clade (which includes the cholesterol side-chain cleavage enzyme CYP11A1). CYP11B2 acts on C21 steroids (deoxycorticosterone and downstream intermediates), well downstream of cholesterol, and does not itself metabolize cholesterol. Reason: Over-broad IBA inherited from cholesterol-metabolizing relatives in the CYP11 family. CYP11B2's substrates are corticosteroids, not cholesterol. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE GRANULARITY MISMATCH Supporting Evidence: PMID:23322723 The structures reveal a hydrophobic cavity with specific features associated with corticosteroid recognition. |
| GO:0047783 corticosterone 18-monooxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Corticosterone 18-monooxygenase / aldosterone synthase activity (EC 1.14.15.5), by phylogeny. This is the diagnostic core activity of CYP11B2: 18-hydroxylation of corticosterone and subsequent 18-oxidation, the steps that distinguish aldosterone synthase from CYP11B1 and yield aldosterone. Reason: Defining molecular function; the additional 18-oxidase activity is the feature that separates CYP11B2 from the otherwise near-identical CYP11B1. Supporting Evidence: PMID:23322723 most of the divergent residues that confer additional 18-oxidase activity of aldosterone synthase are located in the PMID:2256920 P-450aldo preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO monooxygenase activity from cytochrome P450 domain signatures. Correct general P450 activity; a parent of the specific steroid monooxygenase functions CYP11B2 performs. Reason: Accurate general molecular function inferred from P450 domains; broader than the specific EC-level terms but not misleading. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Aldosterone synthase |
| GO:0004507 steroid 11-beta-monooxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt automatic (RHEA/EC 1.14.15.4) mapping to steroid 11-beta-monooxygenase activity. Consistent with the experimentally established 11-beta-hydroxylase activity of CYP11B2. Reason: Correct EC-based electronic annotation matching curated catalytic activity. Supporting Evidence: PMID:23322723 explains the high 11Ξ²-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO iron ion binding, from the P450 heme-iron center. CYP11B2 binds a heme whose iron is coordinated by an axial cysteine thiolate (Cys450). Reason: Correct; the catalytic heme iron is an integral cofactor. Secondary/enabling molecular function supporting the monooxygenase chemistry. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt /ligand_part="Fe" |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt automatic mitochondrion localization. Correct but less specific than the mitochondrial inner membrane where CYP11B2 acts. Reason: Accurate parent localization; the more informative term is mitochondrial inner membrane (also annotated). Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location keyword mapping to mitochondrial inner membrane. This is the specific, correct site of CYP11B2 action. Reason: Matches curated UniProt subcellular location and Reactome; core CC. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane |
| GO:0016125 sterol metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA electronic annotation to sterol metabolic process. CYP11B2 metabolizes C21 corticosteroids (deoxycorticosterone and downstream intermediates), not free sterols/cholesterol. Reason: Over-broad rule-based annotation inherited from steroidogenic P450 context; the enzyme's substrates are corticosteroids, not sterols per se. Supporting Evidence: PMID:23322723 The structures reveal a hydrophobic cavity with specific features associated with corticosteroid recognition. |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO oxidoreductase activity (paired-donor, O2-incorporating), i.e. the general monooxygenase chemistry of a P450. Accurate parent term. Reason: Correct general catalytic class for a cytochrome P450 monooxygenase. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt A cytochrome P450 monooxygenase that catalyzes the |
| GO:0020037 heme binding | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt automatic heme binding annotation. CYP11B2 is a heme-thiolate cytochrome P450; heme is its catalytic cofactor. Reason: Correct; supported experimentally by the crystal structure with heme. Secondary/enabling function underlying the monooxygenase activity. Supporting Evidence: PMID:23322723 we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone |
| GO:0032342 aldosterone biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation to aldosterone biosynthetic process, consistent with the enzyme's defining physiological role. Reason: Correct core BP, corroborating the experimental and phylogenetic annotations. Supporting Evidence: PMID:2256920 P-450aldo preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone |
| GO:0047783 corticosterone 18-monooxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt automatic (RHEA/EC 1.14.15.5) mapping to corticosterone 18-monooxygenase (aldosterone synthase) activity. Matches curated catalytic activity and is the diagnostic CYP11B2 function. Reason: Correct EC-based electronic annotation of the defining 18-oxidase activity. Supporting Evidence: PMID:23322723 most of the divergent residues that confer additional 18-oxidase activity of aldosterone synthase are located in the |
| GO:0006705 mineralocorticoid biosynthetic process | TAS Reactome:R-HSA-193993 | ACCEPT | Summary: Reactome TAS to mineralocorticoid biosynthetic process. Aldosterone is the major human mineralocorticoid, synthesized from deoxycorticosterone in a three-reaction sequence catalyzed by CYP11B2. Reason: Correct core BP (parent of aldosterone biosynthesis); authoritative Reactome pathway assertion. Supporting Evidence: Reactome:R-HSA-193993 which in turn is converted to aldosterone in a three-reaction sequence catalyzed by CYP11B2 |
| GO:0016125 sterol metabolic process | TAS Reactome:R-HSA-211976 | MARK AS OVER ANNOTATED | Summary: Reactome "Endogenous sterols" TAS grouping many CYPs under sterol metabolism. CYP11B2 acts on corticosteroids rather than free sterols; the grouping is over-broad for this specific enzyme. Reason: Pathway-grouping annotation; too general for the corticosteroid-specific catalysis of CYP11B2. Supporting Evidence: PMID:23322723 The structures reveal a hydrophobic cavity with specific features associated with corticosteroid recognition. |
| GO:0004507 steroid 11-beta-monooxygenase activity | TAS Reactome:R-HSA-194017 | ACCEPT | Summary: Reactome TAS for the reaction "CYP11B2 oxidises 11DCORST to CORST" - 11-beta-hydroxylation of 11-deoxycorticosterone to corticosterone. Reason: Correct core MF backed by an authoritative Reactome reaction. Supporting Evidence: Reactome:R-HSA-194017 The 11-beta oxidation of 11-deoxycorticosterone (11DCORST) leads to corticosterone (CORST) |
| GO:0004507 steroid 11-beta-monooxygenase activity | TAS Reactome:R-HSA-5600598 | ACCEPT | Summary: Reactome TAS (disease reaction "Defective CYP11B2 does not oxidise 11DCORST") annotating the normal 11-beta-monooxygenase activity of CYP11B2. Reason: Correct core MF; duplicate of the same activity from a disease-variant reaction, but the underlying enzymatic assertion is sound. Supporting Evidence: Reactome:R-HSA-5600598 CYP11B2 aka aldosterone hydroxylase) is an enzyme necessary for aldosterone biosynthesis via corticosterone (CORST) |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of mitochondrial inner-membrane localization from an ortholog (UniProtKB:P14137, bovine CYP11B). Consistent with human UniProt location. Reason: Correct core CC, corroborated by curated UniProt subcellular location and Reactome. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial-proteome detection places CYP11B2 in the mitochondrion. Consistent with its known mitochondrial inner-membrane localization. Reason: Correct, corroborating mitochondrial localization; less specific than the inner-membrane term. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-5600598 | ACCEPT | Summary: Reactome TAS placing CYP11B2 catalysis at the mitochondrial inner membrane. Reason: Correct core CC from an authoritative pathway source. Supporting Evidence: Reactome:R-HSA-193995 This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6785244 | ACCEPT | Summary: Reactome TAS (disease reaction) placing CYP11B2 at the mitochondrial inner membrane. Reason: Correct core CC; duplicate localization from a disease-variant reaction. Supporting Evidence: Reactome:R-HSA-193995 This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-6785245 | ACCEPT | Summary: Reactome TAS (disease reaction) placing CYP11B2 at the mitochondrial inner membrane. Reason: Correct core CC; duplicate localization from a disease-variant reaction. Supporting Evidence: Reactome:R-HSA-193995 This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-193965 | ACCEPT | Summary: Reactome TAS (reaction "CYP11B2 oxidises 18HCORST to ALDO") placing CYP11B2 at the mitochondrial inner membrane. Reason: Correct core CC from an authoritative pathway reaction. Supporting Evidence: Reactome:R-HSA-193965 This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-193995 | ACCEPT | Summary: Reactome TAS (reaction "CYP11B2 18-hydroxylates CORST to 18HCORST") placing CYP11B2 at the mitochondrial inner membrane. Reason: Correct core CC from an authoritative pathway reaction. Supporting Evidence: Reactome:R-HSA-193995 This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-194017 | ACCEPT | Summary: Reactome TAS (reaction "CYP11B2 oxidises 11DCORST to CORST") placing CYP11B2 at the mitochondrial inner membrane. Reason: Correct core CC from an authoritative pathway reaction. Supporting Evidence: Reactome:R-HSA-194017 Cytochrome P450 11B2, mitochondrial |
| GO:0008395 steroid hydroxylase activity | TAS Reactome:R-HSA-193965 | ACCEPT | Summary: Reactome TAS grouping CYP11B2's activity under steroid hydroxylase activity. Correct parent term encompassing its 11-beta- and 18-hydroxylase activities. Reason: Accurate grouping MF; the specific EC-level terms (11-beta- and 18-monooxygenase) are the more informative core functions. Supporting Evidence: Reactome:R-HSA-193965 18-Hydroxycorticosterone and NADPH + H+ react to form aldosterone |
| GO:0008395 steroid hydroxylase activity | TAS Reactome:R-HSA-193995 | ACCEPT | Summary: Reactome TAS grouping CYP11B2 under steroid hydroxylase activity (from the 18-hydroxylation reaction). Correct parent term. Reason: Accurate grouping MF; duplicate of the same activity from another reaction. 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 | ACCEPT | Summary: Reactome TAS (disease reaction) grouping CYP11B2 under steroid hydroxylase activity. Reason: Accurate grouping MF; duplicate from a disease-variant reaction. Supporting Evidence: Reactome:R-HSA-6785244 CYP11B2 aka aldosterone hydroxylase) is an enzyme necessary for aldosterone biosynthesis |
| GO:0008395 steroid hydroxylase activity | TAS Reactome:R-HSA-6785245 | ACCEPT | Summary: Reactome TAS (disease reaction) grouping CYP11B2 under steroid hydroxylase activity. Reason: Accurate grouping MF; duplicate from a disease-variant reaction. Supporting Evidence: Reactome:R-HSA-6785245 CYP11B2 aka aldosterone hydroxylase) is an enzyme necessary for aldosterone biosynthesis |
| GO:0004507 steroid 11-beta-monooxygenase activity | IDA PMID:23322723 Structural insights into aldosterone synthase substrate spec... | ACCEPT | Summary: Direct assay/structure of human aldosterone synthase demonstrating high 11-beta-hydroxylase activity, with the substrate deoxycorticosterone bound in the crystal structure. Reason: Strong experimental (IDA) support from crystallography plus biochemistry. Core molecular function. Supporting Evidence: PMID:23322723 explains the high 11Ξ²-hydroxylase activity of aldosterone synthase toward both gluco- and mineralocorticoid formation |
| GO:0020037 heme binding | IDA PMID:23322723 Structural insights into aldosterone synthase substrate spec... | ACCEPT | Summary: Direct structural demonstration of heme binding: the crystal structures contain the heme cofactor with iron coordinated by an axial cysteine. Reason: Experimentally confirmed cofactor binding (IDA); secondary/enabling MF underlying the monooxygenase catalysis. Supporting Evidence: PMID:23322723 we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone |
| GO:0032342 aldosterone biosynthetic process | IDA PMID:23322723 Structural insights into aldosterone synthase substrate spec... | ACCEPT | Summary: Direct evidence that CYP11B2 is the sole enzyme producing aldosterone in humans, catalyzing formation of aldosterone from deoxycorticosterone. Reason: Core BP supported by direct biochemical/structural study. Supporting Evidence: PMID:23322723 Aldosterone synthase (cytochrome P450 11B2, CYP11B2) is the sole enzyme responsible for the production of aldosterone in humans. |
| GO:0035865 cellular response to potassium ion | IEP PMID:19342457 Regulation of aldosterone and cortisol production by the tra... | KEEP AS NON CORE | Summary: Expression-pattern (IEP) evidence that CYP11B2 transcription responds to extracellular potassium (K+), via T-type calcium channel (Cav3.2/CACNA1H) signaling and NRSF/NRSE regulation, increasing aldosterone output. Reason: Reflects transcriptional/physiological regulation of the gene by K+ rather than a molecular activity of the enzyme; real but peripheral to core function. Supporting Evidence: PMID:19342457 NRSF/NRSE is also involved in angiotensin II- and K(+)-stimulated augmentation of CYP11B2 and CYP11B1 gene transcription. |
| GO:0032342 aldosterone biosynthetic process | IMP PMID:19342457 Regulation of aldosterone and cortisol production by the tra... | ACCEPT | Summary: Mutation/perturbation (IMP) evidence: modulating CYP11B2 expression (via NRSF inhibition) changes aldosterone secretion in human adrenocortical cells, supporting its role in aldosterone biosynthesis. Reason: Core BP; consistent with the enzyme's defining function. Supporting Evidence: PMID:19342457 increased human CYP11B2 and CYP11B1 mRNA expression, leading to aldosterone and cortisol secretion in human adrenocortical (H295R) cells |
| GO:0032870 cellular response to hormone stimulus | IEP PMID:19342457 Regulation of aldosterone and cortisol production by the tra... | KEEP AS NON CORE | Summary: Expression-pattern (IEP) evidence that CYP11B2 transcription responds to hormonal stimulation (e.g. angiotensin II), consistent with regulation of aldosterone production. Reason: Regulatory/physiological response term, not a molecular function of the protein; peripheral to core enzymatic role. Supporting Evidence: PMID:19342457 NRSF/NRSE is also involved in 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... | MARK AS OVER ANNOTATED | Summary: IMP annotation to cortisol biosynthesis from a study where NRSF inhibition increased both CYP11B2 and CYP11B1 expression and both aldosterone and cortisol secretion in H295R cells. Physiological cortisol production is driven by the paralog CYP11B1, not CYP11B2. Reason: The cortisol readout in this experiment reflects the co-induced CYP11B1 (and possibly low-level in-vitro CYP11B2 activity), not the physiological role of CYP11B2. This is contradicted by the BHF-UCL NOT|involved_in cortisol biosynthesis annotation and by the CYP11B1/CYP11B2 division of labor, so it is flagged as an over-annotation rather than a core function. Supporting Evidence: PMID:19342457 Aldosterone synthase (CYP11B2) and 11 beta-hydroxylase (CYP11B1) regulate aldosterone and cortisol production, respectively. |
| GO:0034651 cortisol biosynthetic process | IMP NOT PMID:9703385 Molecular genetic study in two patients with congenital hypo... | ACCEPT | Summary: NOT|involved_in cortisol biosynthetic process. In CMO-deficiency patients, cortisol and its precursors are in the normal range despite defective aldosterone synthesis, indicating CYP11B2 is not required for cortisol production (that is the role of CYP11B1). Reason: Correct negation: CYP11B2 loss does not impair cortisol biosynthesis, consistent with the CYP11B1/CYP11B2 division of labor. This negated annotation is well supported and appropriately curated. Supporting Evidence: PMID:9703385 Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. |
| 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: IMP from CMO-II deficiency patients: CYP11B2 loss-of-function reduces aldosterone, causing salt-wasting and disturbed volume/electrolyte balance, linking the enzyme to aldosterone-mediated regulation of blood volume. Reason: A downstream physiological consequence of aldosterone production, not the enzyme's molecular core function; retained as a non-core organismal role. Supporting Evidence: PMID:14614232 Japanese patients newly diagnosed with CMO II deficiency |
| GO:0003091 renal water homeostasis | IC PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | KEEP AS NON CORE | Summary: Curator inference (IC, from aldosterone biosynthetic process) that CYP11B2, by producing aldosterone, contributes to renal water homeostasis. Reason: Downstream physiological consequence of aldosterone action on the kidney; not the enzyme's molecular core function. Supporting Evidence: PMID:2256920 P-450aldo preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone |
| GO:0004507 steroid 11-beta-monooxygenase activity | IDA PMID:1741400 Role of steroid 11 beta-hydroxylase and steroid 18-hydroxyla... | ACCEPT | Summary: Direct assay: CYP11B2 (P-450C18) expressed in COS-7 cells exhibits steroid 11-beta-hydroxylase activity in addition to 18-hydroxylase activity. Reason: Core molecular function supported by direct heterologous-expression assay. Supporting Evidence: PMID:1741400 exhibits steroid 18-hydroxylase activity to catalyze the synthesis of aldosterone and 18-oxocortisol and exhibits steroid 11 beta-hydroxylase activity as well. |
| GO:0004507 steroid 11-beta-monooxygenase activity | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: Direct assay: P-450aldo (CYP11B2) expressed in COS-7 cells forms corticosterone from 11-deoxycorticosterone (11-beta-hydroxylation). Reason: Core molecular function supported by direct heterologous-expression assay. Supporting Evidence: PMID:2256920 both enzymes catalyze the formation of corticosterone and 18-hydroxy-11-deoxycorticosterone using 11-deoxycorticosterone as a substrate |
| GO:0005739 mitochondrion | IDA PMID:1741400 Role of steroid 11 beta-hydroxylase and steroid 18-hydroxyla... | ACCEPT | Summary: IDA mitochondrion localization from expression studies of CYP11B2, a mitochondrial P450. Consistent with the curated inner-membrane location. Reason: Correct localization; less specific than the mitochondrial inner membrane. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IC PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: Curator inference (IC, from steroid 11-beta-monooxygenase activity) placing CYP11B2 at the mitochondrial inner membrane, where mitochondrial P450s and the adrenodoxin electron system operate. Reason: Correct core CC; consistent with UniProt subcellular location and Reactome. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane |
| GO:0006700 C21-steroid hormone biosynthetic process | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: IDA to C21-steroid hormone biosynthesis: CYP11B2 synthesizes aldosterone (a C21 corticosteroid) from 11-deoxycorticosterone via corticosterone and 18-hydroxycorticosterone. Reason: Correct broader biosynthetic BP; aldosterone is a C21 steroid hormone. Supporting Evidence: PMID:2256920 P-450aldo preferentially catalyzes the 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: Curator inference (IC, from steroid 11-beta-monooxygenase activity) that CYP11B2 binds heme, as expected for a cytochrome P450. Reason: Correct; heme is the catalytic cofactor, later confirmed structurally (PMID:23322723). Secondary/enabling MF. Supporting Evidence: PMID:23322723 we present the crystal structures of human aldosterone synthase in complex with a substrate deoxycorticosterone |
| GO:0032342 aldosterone biosynthetic process | IDA PMID:1741400 Role of steroid 11 beta-hydroxylase and steroid 18-hydroxyla... | ACCEPT | Summary: Direct assay: CYP11B2 catalyzes the synthesis of aldosterone (via its 18-hydroxylase/18-oxidase activity), unlike CYP11B1 which cannot. Reason: Core BP directly demonstrated by heterologous expression. Supporting Evidence: PMID:1741400 exhibits steroid 18-hydroxylase activity to catalyze the synthesis of aldosterone and 18-oxocortisol |
| GO:0032342 aldosterone biosynthetic process | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: Direct assay: P-450aldo (CYP11B2) preferentially converts 11-deoxycorticosterone to aldosterone, unlike P-450(11)beta (CYP11B1). Reason: Core BP directly demonstrated; this study distinguishes CYP11B2 from CYP11B1 by the aldosterone-forming capacity. Supporting Evidence: PMID:2256920 P-450aldo preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone |
| GO:0055075 potassium ion homeostasis | IMP PMID:9838244 Homozygous deletion of arginine-173 in the CYP11B2 gene in a... | KEEP AS NON CORE | Summary: IMP from a CMO-II deficiency patient with homozygous R173 deletion: loss of aldosterone synthase activity causes elevated plasma potassium (and low sodium), linking CYP11B2 to potassium homeostasis via aldosterone. Reason: Downstream physiological consequence of aldosterone deficiency, not the enzyme's molecular core function. Supporting Evidence: PMID:9838244 Important laboratory findings were 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: IMP from a CMO-II deficiency patient: loss of aldosterone synthase causes salt-wasting with low plasma sodium, linking CYP11B2 to sodium homeostasis via aldosterone. Reason: Downstream physiological consequence of aldosterone deficiency, not the enzyme's molecular core function. Supporting Evidence: PMID:9838244 Salt wasting was caused by an enzymatic defect in the terminal aldosterone biosynthesis. |
| GO:0005739 mitochondrion | IDA PMID:2256920 Cloning and expression of a cDNA for human cytochrome P-450a... | ACCEPT | Summary: IDA mitochondrion localization from expression studies of P-450aldo (CYP11B2), a mitochondrial cytochrome P450. Reason: Correct localization; less specific than the mitochondrial inner membrane. Supporting Evidence: file:human/CYP11B2/CYP11B2-uniprot.txt Mitochondrion inner membrane |
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