CYP11A1 (cytochrome P450 family 11 subfamily A member 1; also known as P450scc, cholesterol side-chain cleavage enzyme, or cholesterol desmolase; EC 1.14.15.6) is a mitochondrial inner-membrane, heme-thiolate cytochrome P450 monooxygenase. It catalyzes the first and rate-limiting enzymatic step of steroidogenesis: the conversion of cholesterol to pregnenolone, the common precursor of all steroid hormones. Catalysis proceeds through three sequential mono-oxygenation reactions on the cholesterol side chain (22-hydroxylation, 20-hydroxylation to give 20R,22R-dihydroxycholesterol, and scission of the C20-C22 bond) yielding pregnenolone and 4-methylpentanal. The enzyme receives electrons from NADPH through the mitochondrial ferredoxin electron-transfer system, comprising adrenodoxin reductase (FDXR) and adrenodoxin/ferredoxin (FDX1/FDX2), which docks onto CYP11A1 to deliver electrons to its heme iron. CYP11A1 is anchored to the matrix-facing side of the mitochondrial inner membrane and is highly expressed in steroidogenic tissues (adrenal cortex, gonads, placenta). Loss-of-function mutations cause congenital adrenal insufficiency with 46,XY sex reversal (AICSR), a lipoid congenital adrenal hyperplasia-like disorder in which impaired cleavage of cholesterol blocks synthesis of all adrenal and gonadal steroids.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006704 glucocorticoid biosynthetic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic (IBA) annotation to glucocorticoid biosynthesis. CYP11A1 is required upstream of glucocorticoid synthesis, but its own molecular activity is conversion of cholesterol to pregnenolone; the downstream glucocorticoid-specific steps (e.g. CYP11B1, CYP21A2) are carried out by other enzymes. Reason: CYP11A1 produces pregnenolone, the common precursor of ALL steroid classes, and is not committed to the glucocorticoid branch. Annotating it to glucocorticoid biosynthetic process attributes a downstream, branch-specific process to an enzyme that acts at the pathway entry point. The core biosynthetic role is better captured by C21-steroid hormone biosynthetic process (GO:0006700), steroid hormone biosynthetic process (GO:0120178) and cholesterol metabolic process (GO:0008203). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones |
| 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 | MARK AS OVER ANNOTATED | Summary: Phylogenetic (IBA) annotation to cortisol metabolism. As with glucocorticoid biosynthesis, cortisol is a downstream product; CYP11A1 acts at the pathway entry step and is not cortisol-specific. Reason: Cortisol is synthesized several steps downstream of pregnenolone by dedicated enzymes. Attributing cortisol metabolic process to CYP11A1 over-specifies its role; its contribution is upstream provision of pregnenolone for all steroid branches. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones |
| 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: CYP11A1 expression is induced by cAMP/ACTH signaling, so participation in the cellular response to peptide hormone stimulus is biologically reasonable but peripheral to its core enzymatic function; retain as non-core. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt INDUCTION: 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 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) mapping to the generic monooxygenase activity parent. Correct but much less informative than the specific cholesterol monooxygenase (side-chain- cleaving) activity (GO:0008386). Reason: CYP11A1 is a monooxygenase, so the term is not wrong, but it is a high-level parent that is subsumed by the specific GO:0008386 annotation already present. Retaining it as core would over-generalize the enzyme's function. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt A cytochrome P450 monooxygenase that catalyzes the side-chain |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO (IEA) annotation for iron-ion binding, reflecting the catalytic heme iron of this cytochrome P450. Reason: The iron bound by CYP11A1 is the heme iron (axial Cys462 thiolate ligand). Iron ion binding is a correct supporting molecular function but is a facet of heme binding (GO:0020037), which more precisely captures the cofactor; keep as non-core. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt /ligand="heme" |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA (IEA) localization to the mitochondrion. Correct but broader than the specific mitochondrial inner membrane localization. Reason: CYP11A1 is a mitochondrial protein; the annotation is correct but the more specific mitochondrial inner membrane term (GO:0005743) better captures its location. Retain as non-core parent. 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 EC=1.14.15.6 |
| GO:0008395 steroid hydroxylase activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA (IEA) annotation to the generic steroid hydroxylase activity. CYP11A1 does hydroxylate its steroid substrate, but the specific side-chain-cleaving activity (GO:0008386) is more informative. Reason: Steroid hydroxylase activity is a broad parent capturing the two hydroxylation steps, but CYP11A1's diagnostic function includes the subsequent C-C bond cleavage and is fully captured by GO:0008386. Retaining this generic term as core would under-specify the function. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt Catalyzes three sequential oxidation reactions of cholesterol, namely the hydroxylation |
| GO:0016125 sterol metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA (IEA) annotation to sterol metabolic process, a correct broad parent of cholesterol metabolic process. Reason: Cholesterol is a sterol and is the CYP11A1 substrate, so sterol metabolic process is correct but broader than the cholesterol metabolic process (GO:0008203) annotation; retain as non-core. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt PATHWAY: Steroid metabolism; cholesterol metabolism. |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) mapping to a high-level P450 oxidoreductase parent term. Correct but generic. Reason: This broad oxidoreductase parent describes the general P450 chemistry and is subsumed by the specific cholesterol monooxygenase (side-chain-cleaving) activity already annotated; it over-generalizes the molecular function. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt A cytochrome P450 monooxygenase that catalyzes the side-chain |
| 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 | MARK AS OVER ANNOTATED | Summary: ARBA (IEA) mapping to a mechanistic oxidoreductase parent describing use of a reduced iron-sulfur protein (adrenodoxin) as electron donor. Correct but more generic than GO:0008386. Reason: This term accurately describes the mitochondrial-P450 mechanism (electrons from the iron-sulfur protein adrenodoxin), but it is a broad functional parent subsumed by the specific cholesterol side-chain-cleaving activity; retain as over-annotated rather than core. Supporting Evidence: PMID:21636783 the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of CYP11A1 |
| 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 COFACTOR: |
| GO:0005515 protein binding | IPI PMID:25464930 Novel interactive partners of neuroligin 3: new aspects for ... | MARK AS OVER ANNOTATED | Summary: IntAct IPI annotation from a yeast two-hybrid/co-validation screen identifying CYP11A1 as an interactor of neuroligin 3 (NLGN3). This is a bare "protein binding" term with no functional specificity for CYP11A1. Reason: The generic protein binding term conveys no informative molecular function and the supporting interaction (NLGN3 partner from a broad Y2H screen for autism candidates) is not connected to CYP11A1's steroidogenic role. Per curation policy for uninformative bare protein-binding IPIs, mark as over-annotated rather than remove. 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 | KEEP AS NON CORE | Summary: Reactome TAS annotation (Endogenous sterols) to sterol metabolic process. Correct broad parent capturing the enzyme's role in cholesterol/sterol homeostasis. Reason: CYP11A1 uses cholesterol (a sterol) in steroidogenesis, contributing to sterol homeostasis; sterol metabolic process is correct but broader than cholesterol metabolic process, so retain as non-core. Supporting Evidence: Reactome:R-HSA-211976 A number of CYPs take part in cholesterol biosynthesis and elimination, thus playing an important role in maintaining cholesterol homeostasis |
| 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 | KEEP AS NON CORE | Summary: UniPathway (IEA) mapping to C21-steroid hormone metabolic process, the metabolic parent of the C21-steroid hormone biosynthetic process. Reason: Correct broad metabolic parent (pregnenolone is a C21 steroid); the more specific biosynthetic term GO:0006700 better captures the core role, so retain this as non-core. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt PATHWAY: Lipid metabolism; C21-steroid hormone metabolism. |
| 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... | KEEP AS NON CORE | Summary: High-throughput proteomics (HTP) localization to the mitochondrion, from a high-confidence human mitochondrial proteome study (MitoCoP). Consistent with the established mitochondrial localization of CYP11A1. Reason: Supports mitochondrial localization, but the more specific mitochondrial inner membrane term (GO:0005743) better captures CYP11A1's location; retain the broader compartment annotation as non-core. Supporting Evidence: PMID:34800366 defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP) |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-5580269 | KEEP AS NON CORE | Summary: Reactome TAS localization to the mitochondrial matrix. CYP11A1 is a peripheral membrane protein on the matrix-facing side of the inner membrane, and its product pregnenolone is released into the matrix. Reason: Consistent with the matrix-facing orientation described in UniProt; the inner membrane term (GO:0005743) is the primary localization, so retain the matrix annotation as non-core. 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 | KEEP AS NON CORE | Summary: Reactome TAS localization to the mitochondrial matrix, associated with the first side-chain cleavage reaction. Reason: Reflects the matrix-facing orientation of the inner-membrane-associated enzyme; retain as non-core relative to the primary inner membrane localization. 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 | KEEP AS NON CORE | Summary: Reactome TAS localization to the mitochondrial matrix, associated with the second side-chain cleavage reaction. Reason: Reflects the matrix-facing orientation of the inner-membrane-associated enzyme; retain as non-core relative to the primary inner membrane localization. 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 | KEEP AS NON CORE | Summary: Reactome TAS localization to the mitochondrial matrix, associated with the final C-C cleavage step; the product pregnenolone is released into the matrix. Reason: Reflects the matrix-facing orientation of the inner-membrane-associated enzyme and release of pregnenolone into the matrix; retain as non-core relative to the primary inner membrane localization. Supporting Evidence: Reactome:R-HSA-193101 PREG is substantially more hydrophilic than cholesterol (CHOL) and hydroxycholesterol (HCHOL) and is released into the mitochondrial matrix |
| 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: Sequence-similarity (ISS) annotation to vitamin D metabolic process. CYP11A1 can act on vitamin D substrates (e.g. producing hydroxy-vitamin D metabolites, notably in skin), but this is a secondary, non-canonical activity relative to cholesterol side-chain cleavage. Reason: CYP11A1 has documented capacity to metabolize vitamin D compounds, so the annotation is biologically plausible, but it is a minor/secondary function compared to the steroidogenic core role; retain as non-core. Supporting Evidence: file:human/CYP11A1/CYP11A1-uniprot.txt DrugBank; DB00169; Cholecalciferol. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity (ISS) localization to the mitochondrion, transferred from an ortholog. Correct but broader than the mitochondrial inner membrane localization. Reason: Correct compartment but broader than the specific mitochondrial inner membrane annotation; retain as non-core parent. 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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