CYP11A1 is a mitochondrial heme-thiolate monooxygenase that initiates steroid hormone biosynthesis by converting cholesterol to pregnenolone. At the matrix face of the inner mitochondrial membrane it performs successive C22 and C20 hydroxylations and C20–C22 bond cleavage, releasing pregnenolone and 4-methylpentanal. Electrons are supplied from NADPH through ferredoxin reductase and adrenodoxin. This shared entry reaction supports adrenal, gonadal and placental steroidogenesis; tissue-specific downstream enzymes determine the final hormones. CYP11A1 also supports a secondary pathway of vitamin D hydroxylation. Loss-of-function variants can cause combined adrenal and gonadal steroid deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006704 glucocorticoid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: CYP11A1 catalyzes the entry reaction of adrenal glucocorticoid biosynthesis. Reason: Pregnenolone synthesis is an actual enzymatic step within the multistep glucocorticoid pathway. A shared upstream reaction need not be glucocorticoid-specific to participate; the prior over-annotation judgment incorrectly excluded pathway-entry enzymes. Human CYP11A1 biochemistry and adrenal-deficiency variants support the PAINT-inherited role. Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) PMID:18182448 Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone in all steroidogenic tissues |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the defining CYP11A1 molecular function: cholesterol side-chain-cleaving monooxygenase (P450scc). This is the core molecular function and is strongly supported experimentally. Reason: This is the diagnostic activity of CYP11A1/P450scc (EC 1.14.15.6), consistent across IBA, IEA, ISS, TAS and direct experimental (IDA) evidence, and with the structurally and biochemically characterized reaction. Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) |
| GO:0034650 cortisol metabolic process | IBA GO_REF:0000033 | MODIFY | Summary: CYP11A1 contributes to the biosynthetic branch of cortisol metabolism. Reason: Refine the broad cortisol-metabolism assertion to cortisol biosynthesis: CYP11A1 directly makes its upstream pregnenolone precursor in adrenal steroidogenesis. This does not assign cortisol hydroxylase activity or cortisol catabolism to CYP11A1. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001547321 SUPPORTS TRANSFER Cached PAINT identifies the supporting IBD at this node. The broad inherited biological claim remains supported; refinement specifies the biosynthetic process documented by target evidence rather than rejecting the node placement or its descendant evidence. Proposed replacements: cortisol biosynthetic process Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) PMID:18182448 Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone in all steroidogenic tissues |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) localization to the mitochondrial inner membrane, where P450scc is active. This is the established site of action of CYP11A1. Reason: CYP11A1 is a peripheral membrane protein on the matrix-facing side of the mitochondrial inner membrane, where it acts together with the ferredoxin system. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006700 C21-steroid hormone biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to C21-steroid hormone biosynthesis. Pregnenolone (the CYP11A1 product) is a C21 steroid, and CYP11A1 initiates the C21-steroid hormone biosynthetic pathway. Reason: CYP11A1 catalyzes the committed entry step of C21-steroid hormone biosynthesis by converting cholesterol to pregnenolone; this is a core biological process for the gene and is supported by IBA, IDA, IEA and TAS evidence. Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol |
| GO:0071375 cellular response to peptide hormone stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) annotation reflecting that steroidogenic expression/activity of P450scc is regulated by peptide hormones (e.g. ACTH via cAMP). This is a regulatory cellular response rather than a molecular activity of CYP11A1. Reason: Retain the conserved cellular-response context as peripheral to catalysis: steroidogenic cells use CYP11A1 as an effector of hormone/cAMP-regulated steroid output, not a peptide receptor or signal transducer. PMID:1849407 demonstrates cAMP-responsive CYP11A1 synthesis in human JEG-3 and mouse Y1 cells; cAMP is a downstream messenger rather than a direct peptide-ligand assay. Supporting Evidence: PMID:1849407 The production of P-450scc in Y1 and JEG-3 cells was stimulated by 8-bromo cyclic AMP |
| GO:0008203 cholesterol metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to cholesterol metabolism. CYP11A1 consumes cholesterol as its substrate, converting it to pregnenolone. Reason: Cholesterol is the direct substrate of CYP11A1; its side-chain cleavage is a core cholesterol metabolic (catabolic/utilization) process. Supported by IBA, IDA, ISS and IEA evidence. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt PATHWAY: Steroid metabolism; cholesterol metabolism. |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000002 | MODIFY | Summary: The broad oxidoreductase class is supported, with a characterized cholesterol side-chain-cleavage activity. Reason: Refine this true enzymatic parent to the existing GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity. The reaction uses a reduced ferredoxin donor and includes two hydroxylations before carbon-carbon bond scission; broadness alone is not evidence of over-annotation. Proposed replacements: cholesterol monooxygenase (side-chain-cleaving) activity Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) file:human/CYP11A1/CYP11A1-uniprot.txt Two electrons are provided by NADPH via a two-protein mitochondrial transfer system |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: CYP11A1 binds iron as part of its catalytic heme. Reason: The experimentally resolved heme iron is an essential part of core cytochrome P450 catalysis. Retain metal binding as a cofactor property without implying free-iron transport or a separate iron-storage function. Supporting Evidence: PMID:21636783 the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of CYP11A1 |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: CYP11A1 has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: The electronic organelle annotation is corroborated by curated CYP11A1 mitochondrial localization. The record explicitly distinguishes the matrix-facing inner-membrane position; that specificity is separately annotated and does not replace the informative root organelle. The curated location itself is based on similarity evidence. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location (IEA) mapping to the mitochondrial inner membrane, the established location of CYP11A1. Reason: Consistent with IBA and ISS evidence and the UniProt subcellular location; this is the core localization of the enzyme. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006700 C21-steroid hormone biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA (IEA) annotation to C21-steroid hormone biosynthesis, consistent with the IBA/IDA/TAS annotations to the same term. Reason: Duplicate of the well-supported core biological process; CYP11A1 initiates C21-steroid hormone biosynthesis by producing pregnenolone. Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined-IEA (RHEA/EC 1.14.15.6) mapping to the core cholesterol monooxygenase (side-chain-cleaving) activity. Reason: EC 1.14.15.6 corresponds exactly to the cholesterol side-chain cleavage activity of CYP11A1; this reinforces the core molecular function annotation. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt Reaction=6 reduced [adrenodoxin] + cholesterol + 3 O2 + 6 H(+) = 4-methylpentanal + pregnenolone + 6 oxidized [adrenodoxin] + 4 H2O; |
| GO:0008395 steroid hydroxylase activity | IEA GO_REF:0000117 | MODIFY | Summary: The broad oxidoreductase class is supported, with a characterized cholesterol side-chain-cleavage activity. Reason: Refine this true enzymatic parent to the existing GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity. The reaction uses a reduced ferredoxin donor and includes two hydroxylations before carbon-carbon bond scission; broadness alone is not evidence of over-annotation. Proposed replacements: cholesterol monooxygenase (side-chain-cleaving) activity Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) file:human/CYP11A1/CYP11A1-uniprot.txt Two electrons are provided by NADPH via a two-protein mitochondrial transfer system |
| GO:0016125 sterol metabolic process | IEA GO_REF:0000117 | MODIFY | Summary: CYP11A1 metabolizes cholesterol, a sterol substrate. Reason: Refine this sterol-metabolism parent to the existing cholesterol metabolic process, whose chemistry is directly characterized. The refinement does not deny experimentally reported alternative sterol substrates. Proposed replacements: cholesterol metabolic process Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000002 | MODIFY | Summary: The broad oxidoreductase class is supported, with a characterized cholesterol side-chain-cleavage activity. Reason: Refine this true enzymatic parent to the existing GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity. The reaction uses a reduced ferredoxin donor and includes two hydroxylations before carbon-carbon bond scission; broadness alone is not evidence of over-annotation. Proposed replacements: cholesterol monooxygenase (side-chain-cleaving) activity Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) file:human/CYP11A1/CYP11A1-uniprot.txt Two electrons are provided by NADPH via a two-protein mitochondrial transfer system |
| GO:0016713 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced iron-sulfur protein as one donor, and incorporation of one atom of oxygen | IEA GO_REF:0000117 | MODIFY | Summary: The broad oxidoreductase class is supported, with a characterized cholesterol side-chain-cleavage activity. Reason: Refine this true enzymatic parent to the existing GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity. The reaction uses a reduced ferredoxin donor and includes two hydroxylations before carbon-carbon bond scission; broadness alone is not evidence of over-annotation. Proposed replacements: cholesterol monooxygenase (side-chain-cleaving) activity Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) file:human/CYP11A1/CYP11A1-uniprot.txt Two electrons are provided by NADPH via a two-protein mitochondrial transfer system |
| GO:0020037 heme binding | IEA GO_REF:0000120 | ACCEPT | Summary: Combined-IEA annotation for heme binding, the essential cofactor of this heme-thiolate cytochrome P450. Reason: CYP11A1 binds heme via an axial cysteine thiolate (Cys462); heme binding is an essential supporting molecular function, confirmed experimentally (IDA) and by crystal structures. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt Name=heme; Xref=ChEBI:CHEBI:30413; |
| GO:0005515 protein binding | IPI PMID:25464930 Novel interactive partners of neuroligin 3: new aspects for ... | REMOVE | Summary: The reported neuroligin-3 association does not define a specific CYP11A1 molecular function. Reason: The original interaction study includes CYP11A1, so the interaction is not dismissed as a wrong-gene claim. Bare protein binding is uninformative under the protein-binding policy; remove this term without inferring a specific receptor-binding or signaling function. Supporting Evidence: PMID:25464930 The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA, ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated |
| GO:0120178 steroid hormone biosynthetic process | IDA PMID:21636783 Structural basis for pregnenolone biosynthesis by the mitoch... | ACCEPT | Summary: Direct experimental (IDA) annotation to steroid hormone biosynthetic process, supported by the structural/biochemical characterization of pregnenolone biosynthesis by the CYP11A1-adrenodoxin complex. Reason: CYP11A1 produces pregnenolone, the precursor of all steroid hormones, thereby initiating steroid hormone biosynthesis. This is a core biological process for the gene. Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol |
| GO:0006700 C21-steroid hormone biosynthetic process | TAS Reactome:R-HSA-196108 | ACCEPT | Summary: Reactome TAS annotation (Pregnenolone biosynthesis) to C21-steroid hormone biosynthesis, consistent with the well-supported core biological process. Reason: Reactome documents CYP11A1 as the enzyme converting cholesterol to pregnenolone in the inner mitochondrial membrane, the entry step of C21-steroid hormone biosynthesis. Supporting Evidence: Reactome:R-HSA-196108 cholesterol is converted to pregnenolone in a sequence of three reactions, all catalyzed by CYP11A (side chain cleavage enzyme) |
| GO:0016125 sterol metabolic process | TAS Reactome:R-HSA-211976 | MODIFY | Summary: CYP11A1 metabolizes cholesterol, a sterol substrate. Reason: Refine this sterol-metabolism parent to the existing cholesterol metabolic process, whose chemistry is directly characterized. The refinement does not deny experimentally reported alternative sterol substrates. Proposed replacements: cholesterol metabolic process Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway (IEA) mapping to cholesterol metabolic process, consistent with the IBA/IDA/ISS annotations to the same term. Reason: Cholesterol is the CYP11A1 substrate; its metabolism is a core process. Duplicate of the experimentally-supported cholesterol metabolic process annotation. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt PATHWAY: Steroid metabolism; cholesterol metabolism. |
| GO:0008207 C21-steroid hormone metabolic process | IEA GO_REF:0000041 | MODIFY | Summary: CYP11A1 produces the C21 steroid pregnenolone. Reason: Refine the broad metabolic term to the existing C21-steroid hormone biosynthetic process. The enzyme executes synthesis rather than merely affecting steroid abundance indirectly. Proposed replacements: C21-steroid hormone biosynthetic process Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol by an enzyme complex comprising adrenodoxin reductase (AdR), adrenodoxin (Adx), and a cytochrome P450 (P450scc or CYP11A1) |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | TAS Reactome:R-HSA-193054 | ACCEPT | Summary: Reactome TAS annotation for the first hydroxylation step (cholesterol to 22beta-hydroxycholesterol) catalyzed by CYP11A1, supporting the core cholesterol side-chain-cleaving activity. Reason: Reactome documents this as the first of the three CYP11A1-catalyzed reactions of the side-chain cleavage sequence; supports the core molecular function. Supporting Evidence: Reactome:R-HSA-193054 Cholesterol and NADPH + H+ react to form 22beta-hydroxycholesterol, NADP+, and H2O, catalyzed by CYP11A (P450scc) |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | TAS Reactome:R-HSA-193065 | ACCEPT | Summary: Reactome TAS annotation for the second hydroxylation step (22beta-hydroxycholesterol to 20alpha,22beta-hydroxycholesterol) catalyzed by CYP11A1. Reason: Documents the second CYP11A1-catalyzed reaction of the side-chain cleavage sequence; supports the core molecular function. Supporting Evidence: Reactome:R-HSA-193065 22beta-hydroxycholesterol, NADPH + H+, and O2 react to form 20alpha,22beta-hydroxycholesterol, NADP+ and H2O, catalyzed by CYP11A (P450scc) |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | TAS Reactome:R-HSA-193101 | ACCEPT | Summary: Reactome TAS annotation for the final C20-C22 bond cleavage step (20alpha,22beta-dihydroxycholesterol to pregnenolone) catalyzed by CYP11A1. Reason: Documents the C-C bond scission that completes side-chain cleavage to pregnenolone; supports the core molecular function. Supporting Evidence: Reactome:R-HSA-193101 This cleavage reaction is catalysed by CYP11A (P450scc) associated with the inner mitochondrial membrane |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) localization to the mitochondrial inner membrane, transferred from an ortholog. Consistent with the IBA/IEA annotations. Reason: Corroborates the core mitochondrial inner membrane localization of CYP11A1. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: CYP11A1 has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: Retain the mitochondrial-compendium assignment with independent curated CYP11A1 mitochondrial location. No new target-table inspection or detection method is claimed for this row, and organelle-level proteomic evidence need not resolve the inner membrane. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5580269 | ACCEPT | Summary: The active CYP11A1 protein occupies the matrix face of the inner mitochondrial membrane. Reason: The matrix-facing topology describes the active enzyme, not a nonfunctional imported pool as in STAR. Retain this cellular context together with inner-membrane association; do not infer a freely soluble matrix enzyme or use release of a reaction product as protein-localization evidence. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt Localizes to the matrix side of the mitochondrion inner membrane. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-193054 | ACCEPT | Summary: The active CYP11A1 protein occupies the matrix face of the inner mitochondrial membrane. Reason: The matrix-facing topology describes the active enzyme, not a nonfunctional imported pool as in STAR. Retain this cellular context together with inner-membrane association; do not infer a freely soluble matrix enzyme or use release of a reaction product as protein-localization evidence. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt Localizes to the matrix side of the mitochondrion inner membrane. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-193065 | ACCEPT | Summary: The active CYP11A1 protein occupies the matrix face of the inner mitochondrial membrane. Reason: The matrix-facing topology describes the active enzyme, not a nonfunctional imported pool as in STAR. Retain this cellular context together with inner-membrane association; do not infer a freely soluble matrix enzyme or use release of a reaction product as protein-localization evidence. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt Localizes to the matrix side of the mitochondrion inner membrane. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-193101 | ACCEPT | Summary: The active CYP11A1 protein occupies the matrix face of the inner mitochondrial membrane. Reason: The matrix-facing topology describes the active enzyme, not a nonfunctional imported pool as in STAR. Retain this cellular context together with inner-membrane association; do not infer a freely soluble matrix enzyme or use release of a reaction product as protein-localization evidence. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt Localizes to the matrix side of the mitochondrion inner membrane. |
| GO:0008203 cholesterol metabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) annotation to cholesterol metabolic process, transferred from a characterized ortholog. Consistent with the core role. Reason: Corroborates the core cholesterol metabolic process annotation; cholesterol is the direct substrate of CYP11A1. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt PATHWAY: Steroid metabolism; cholesterol metabolism. |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) annotation to the core cholesterol monooxygenase (side-chain-cleaving) activity, transferred from a characterized ortholog. Reason: Corroborates the diagnostic core molecular function of CYP11A1. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt A cytochrome P450 monooxygenase that catalyzes the side-chain |
| GO:0006700 C21-steroid hormone biosynthetic process | IDA PMID:21636783 Structural basis for pregnenolone biosynthesis by the mitoch... | ACCEPT | Summary: Direct experimental (IDA) annotation to C21-steroid hormone biosynthesis, from the structural and biochemical study of pregnenolone biosynthesis by the CYP11A1- adrenodoxin complex with substrate and reaction intermediates. Reason: The study resolved the CYP11A1 reaction sequence converting cholesterol to pregnenolone (a C21 steroid), directly evidencing its role in C21-steroid hormone biosynthesis. Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol |
| GO:0008203 cholesterol metabolic process | IDA PMID:21636783 Structural basis for pregnenolone biosynthesis by the mitoch... | ACCEPT | Summary: Direct experimental (IDA) annotation to cholesterol metabolic process, from the structural/biochemical characterization of CYP11A1 acting on cholesterol. Reason: Cholesterol is the direct substrate whose side chain is cleaved by CYP11A1; the study characterized this reaction, evidencing a core cholesterol metabolic role. Supporting Evidence: PMID:21636783 the precursor to all steroid hormones, pregnenolone, is synthesized from cholesterol |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | IDA PMID:21636783 Structural basis for pregnenolone biosynthesis by the mitoch... | ACCEPT | Summary: Direct experimental (IDA) annotation to the core cholesterol side-chain-cleaving activity, from the crystal structures and mechanistic analysis of CYP11A1 with substrate and reaction intermediates. Reason: The study defined the sequential hydroxylations and C-C bond cleavage of cholesterol catalyzed by CYP11A1, directly evidencing the cholesterol side-chain- cleaving monooxygenase activity. Supporting Evidence: PMID:21636783 allow us to define the mechanism underlying sequential hydroxylations of the cholesterol and suggest the mechanism of C-C bond cleavage |
| GO:0020037 heme binding | IDA PMID:21636783 Structural basis for pregnenolone biosynthesis by the mitoch... | ACCEPT | Summary: Direct experimental (IDA) annotation to heme binding, from the crystal structure resolving the heme iron of CYP11A1 in the redox complex with adrenodoxin. Reason: The structure directly visualized the CYP11A1 heme iron positioned relative to the adrenodoxin [2Fe-2S] cluster, confirming heme binding as an essential cofactor function. Supporting Evidence: PMID:21636783 the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of CYP11A1 |
| GO:0042359 vitamin D metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CYP11A1 also participates in noncanonical vitamin D hydroxylation. Reason: PMID:22683847 identifies CYP11A1-dependent vitamin D metabolites in tissue/cell systems, including endogenous products in human keratinocytes and 20-hydroxyvitamin D3 in human serum. This independently supports a secondary metabolic role, replacing the uninformative DrugBank cross-reference. Do not transfer all purified-enzyme or adrenal assay details to humans when the abstract does not specify species. Supporting Evidence: PMID:22683847 We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3, and 17,20,23(OH)(3)D3 by immortalized human keratinocytes. PMID:22683847 Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: CYP11A1 has supported mitochondrion localization, retained separately from its subcompartment annotations. Reason: The sequence-similarity mitochondrial assignment agrees with curated CYP11A1 localization on the matrix side of the inner membrane. This remains a conserved compartment inference, not a direct topology assay. The supported organelle is core to the enzyme and is not peripheral merely because the membrane term is more specific. Under the root-organelle policy, retain this supported organelle assertion and its separate subcompartment claims. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006700 C21-steroid hormone biosynthetic process | IDA PMID:11502818 Heterozygous mutation in the cholesterol side chain cleavage... | ACCEPT | Summary: Direct experimental (IDA) annotation to C21-steroid hormone biosynthesis. This case report demonstrated that a de novo CYP11A1 mutation abolishing enzyme activity causes adrenal insufficiency and 46,XY sex reversal, confirming CYP11A1's essential role in steroid hormone biosynthesis. Reason: Functional assay of the patient mutation in a P450scc fusion construct showed complete loss of the cholesterol-to-pregnenolone activity, directly evidencing CYP11A1's role in C21-steroid hormone biosynthesis. Supporting Evidence: PMID:11502818 the mitochondrial cholesterol side chain cleavage enzyme, is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone and, thus, is required for the biosynthesis of all steroid hormones |
| GO:0006700 C21-steroid hormone biosynthetic process | IDA PMID:18182448 Severe combined adrenal and gonadal deficiency caused by nov... | ACCEPT | Summary: Direct experimental (IDA) annotation to C21-steroid hormone biosynthesis, from functional analysis of novel CYP11A1 mutations (L141W, V415E) that reduce or abolish P450scc activity and cause combined adrenal and gonadal deficiency. Reason: Functional studies of patient mutations quantified residual P450scc activity (L141W 38%, V415E 0%), directly linking CYP11A1 enzymatic activity to C21-steroid hormone biosynthesis. Supporting Evidence: PMID:18182448 Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone in all steroidogenic tissues |
| GO:0008203 cholesterol metabolic process | IMP PMID:18182448 Severe combined adrenal and gonadal deficiency caused by nov... | ACCEPT | Summary: Mutant-phenotype (IMP) annotation to cholesterol metabolic process, based on functional characterization of CYP11A1 loss-of-function mutations impairing cholesterol conversion. Reason: Patient mutations with reduced/absent P450scc activity impair conversion of cholesterol to pregnenolone, evidencing CYP11A1's role in cholesterol metabolism. Supporting Evidence: PMID:18182448 One patient harbored the novel P450scc missense mutations L141W and V415E, which retained 38 and 0% activity, respectively |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | IDA PMID:11502818 Heterozygous mutation in the cholesterol side chain cleavage... | ACCEPT | Summary: Direct experimental (IDA) annotation to the core cholesterol side-chain-cleaving activity, from functional assay of the patient's CYP11A1 mutation. Reason: The mutant P450scc was assayed in an active fusion-protein system and shown to completely lose enzymatic activity, directly evidencing the cholesterol side-chain-cleaving monooxygenase function. Supporting Evidence: PMID:11502818 inserted into a catalytically active fusion protein of the P450scc system (H2N-P450scc-Adrenodoxin Reductase-Adrenodoxin-COOH), completely inactivating enzymatic activity |
| GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity | IDA PMID:18182448 Severe combined adrenal and gonadal deficiency caused by nov... | ACCEPT | Summary: Direct experimental (IDA) annotation to the core cholesterol side-chain-cleaving activity, quantifying residual activity of patient CYP11A1 mutants. Reason: Functional studies directly measured P450scc catalytic activity of patient mutants (L141W 38%, V415E 0%), evidencing the cholesterol side-chain-cleaving monooxygenase function. Supporting Evidence: PMID:18182448 One patient harbored the novel P450scc missense mutations L141W and V415E, which retained 38 and 0% activity, respectively |
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Download this section (compressed HTML)Q: What is the physiological significance of CYP11A1 vitamin D3 / 7-dehydrocholesterol metabolism (secosteroid production) relative to its canonical steroidogenic role?
Q: Is the CYP11A1-NLGN3 interaction reported in the yeast two-hybrid screen physiologically relevant, or an artifact of the screen?
Experiment: Quantitative steroid-flux (LC-MS/MS) analysis in CYP11A1-null vs. wild-type steroidogenic cells to confirm the block at the cholesterol-to-pregnenolone step.
Type: metabolomics
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