CYP11A1

UniProt ID: P05108
Organism: Homo sapiens
Review Status: INITIALIZED
📝 Provide Detailed Feedback

Gene Description

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.

Existing Annotations Review

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

Core Functions

Cholesterol side-chain cleavage monooxygenase (P450scc): catalyzes the first and rate-limiting enzymatic step of steroidogenesis, converting cholesterol to pregnenolone through three sequential mono-oxygenations at the matrix face of the mitochondrial inner membrane, using electrons delivered by the ferredoxin (adrenodoxin) system.

Molecular Function:
cholesterol monooxygenase (side-chain-cleaving) activity
Directly Involved In:
steroid biosynthetic process
Cellular Locations:
mitochondrial inner membrane
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)

Heme binding: CYP11A1 binds a b-type heme via an axial cysteine thiolate (Cys462), the essential cofactor for its cytochrome P450 monooxygenase chemistry.

Molecular Function:
heme binding
Cellular Locations:
mitochondrial inner membrane
Supporting Evidence:
  • PMID:21636783
    the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of CYP11A1

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
file:human/CYP11A1/CYP11A1-uniprot.txt
UniProtKB entry P05108 (CP11A_HUMAN), Cholesterol side-chain cleavage enzyme, mitochondrial
PMID:11502818
Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency.
PMID:18182448
Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc.
PMID:21636783
Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.
PMID:25464930
Novel interactive partners of neuroligin 3: new aspects for pathogenesis of autism.
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
Reactome:R-HSA-193054
Oxidation of cholesterol to 22beta-hydroxycholesterol
Reactome:R-HSA-193065
Oxidation of 22beta-hydroxycholesterol to 20alpha,22beta-hydroxycholesterol
Reactome:R-HSA-193101
CYP11A1 cleaves 20a,22b-DHCHOL
Reactome:R-HSA-196108
Pregnenolone biosynthesis
Reactome:R-HSA-211976
Endogenous sterols
Reactome:R-HSA-5580269
Defective CYP11A1 does not cleave 20a,22b-DHCHOL

Suggested Questions for Experts

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?

Suggested Experiments

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

📚 Additional Documentation

Notes

(CYP11A1-notes.md)

CYP11A1 (P450scc) review notes

UniProtKB:P05108, HGNC:2590, EC 1.14.15.6. Cholesterol side-chain cleavage enzyme,
mitochondrial. Deep research not available (falcon out of credits, HTTP 402); review
grounded in UniProt (CYP11A1-uniprot.txt), seeded GOA, and cached publications.

Core biology

  • Mitochondrial inner-membrane cytochrome P450 (heme-thiolate). Catalyzes the first and
    rate-limiting enzymatic step of steroidogenesis: conversion of cholesterol to
    pregnenolone, the precursor of all steroid hormones.
  • Three sequential mono-oxygenations: 22-hydroxylation, then 20-hydroxylation to give
    20R,22R-dihydroxycholesterol, then C20–C22 bond scission yielding pregnenolone +
    4-methylpentanal (isocaproaldehyde). [UniProt FUNCTION; PMID:21636783]
  • Receives electrons from NADPH via the mitochondrial ferredoxin system: adrenodoxin
    reductase (FDXR) + adrenodoxin/ferredoxin (FDX1/FDX2). Crystal structure of the
    CYP11A1–Adx complex resolves the electron-transfer geometry (2Fe-2S cluster 17.4 Å
    from heme iron). PMID:21636783
  • Cofactor: heme (axial Cys462 thiolate ligand, per UniProt BINDING feature and PDB
    3N9Y/3N9Z/3NA0/3NA1). Iron-ion binding = heme iron.
  • Localization: mitochondrion inner membrane, matrix-facing (peripheral membrane
    protein). [UniProt SUBCELLULAR LOCATION]
  • Expression: adrenal cortex (HPA "Tissue enriched (adrenal)"), gonad, placenta.

Disease

  • AICSR (adrenal insufficiency, congenital, with 46,XY sex reversal; MIM:613743).
    Loss-of-function CYP11A1 mutations impair all steroidogenesis → adrenal failure;
    46,XY individuals show underandrogenization / sex reversal.
    [PMID:11502818 de novo Gly-Asp insertion after Asp271, complete inactivation;
    PMID:18182448 compound het L141W (38% activity) / V415E (0% activity)]
  • Distinguished from congenital lipoid adrenal hyperplasia (StAR mutations): P450scc
    deficiency does not show the massive adrenal enlargement.

Annotation decisions (summary)

  • CORE MF: GO:0008386 cholesterol monooxygenase (side-chain-cleaving) activity — accept
    all copies (IBA, IEA, TAS, IDA, ISS).
  • Secondary MF: GO:0020037 heme binding (IDA, IEA) accept; GO:0005506 iron ion binding
    (IEA, = heme iron) accept as non-core. Broad P450 MF parents (GO:0004497,
    GO:0016705, GO:0016713, GO:0008395) are correct-but-general → MARK_AS_OVER_ANNOTATED
    (heme_binding + GO:0008386 already capture the specific function).
  • CORE BP: C21-steroid hormone biosynthetic process (GO:0006700), steroid hormone
    biosynthetic process (GO:0120178), cholesterol metabolic process (GO:0008203). Accept.
  • Broader/pathway BP: sterol metabolic process (GO:0016125), C21-steroid hormone
    metabolic process (GO:0008207) accept as non-core (correct parents).
  • Downstream-product BP: glucocorticoid biosynthetic process (GO:0006704), cortisol
    metabolic process (GO:0034650) — CYP11A1 acts upstream of all these; it produces
    pregnenolone, not cortisol/glucocorticoid directly. IBA over-reaches →
    MARK_AS_OVER_ANNOTATED.
  • GO:0042359 vitamin D metabolic process (ISS) — CYP11A1 can act on vitamin D3
    (7-dehydrocholesterol-derived) in vitro/skin, but this is a minor/secondary activity,
    not the core function → KEEP_AS_NON_CORE.
  • GO:0071375 cellular response to peptide hormone stimulus (IBA) — reflects ACTH
    regulation of steroidogenic cells (P450scc induced by cAMP, PMID:1849407), a cellular
    response not a CYP11A1 molecular activity → KEEP_AS_NON_CORE.
  • CC: mitochondrial inner membrane (GO:0005743, IBA/IEA/ISS) core; mitochondrion
    (GO:0005739) accept as non-core (broader); mitochondrial matrix (GO:0005759, Reactome
    TAS) accept as non-core (matrix-facing peripheral membrane protein).
  • GO:0005515 protein binding (IPI, PMID:25464930, NLGN3 Y2H) — bare protein binding,
    uninformative; per policy MARK_AS_OVER_ANNOTATED (not REMOVE).

📄 View Raw YAML

 
id: P05108
gene_symbol: CYP11A1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: P05108-1
- name: '2'
  id: P05108-2
  sequence_note: VSP_045695
existing_annotations:
- term:
    id: GO:0006704
    label: glucocorticoid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        catalyzes the side-chain hydroxylation and cleavage of cholesterol to
        pregnenolone, the precursor of most steroid hormones
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        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)
- term:
    id: GO:0034650
    label: cortisol metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        catalyzes the side-chain hydroxylation and cleavage of cholesterol to
        pregnenolone, the precursor of most steroid hormones
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) localization to the mitochondrial inner membrane, where P450scc
      is active. This is the established site of action of CYP11A1.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Mitochondrion inner membrane
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        the precursor to all steroid hormones, pregnenolone, is synthesized from
        cholesterol
- term:
    id: GO:0071375
    label: cellular response to peptide hormone stimulus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'INDUCTION: By 8-bromo cyclic AMP.'
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to cholesterol metabolism. CYP11A1 consumes
      cholesterol as its substrate, converting it to pregnenolone.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'PATHWAY: Steroid metabolism; cholesterol metabolism.'
- term:
    id: GO:0004497
    label: monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase that catalyzes the side-chain
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IEA) annotation for iron-ion binding, reflecting the catalytic heme
      iron of this cytochrome P450.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: /ligand="heme"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      ARBA (IEA) localization to the mitochondrion. Correct but broader than the specific
      mitochondrial inner membrane localization.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location (IEA) mapping to the mitochondrial inner membrane, the
      established location of CYP11A1.
    action: ACCEPT
    reason: >-
      Consistent with IBA and ISS evidence and the UniProt subcellular location; this is
      the core localization of the enzyme.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Mitochondrion inner membrane
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA (IEA) annotation to C21-steroid hormone biosynthesis, consistent with the
      IBA/IDA/TAS annotations to the same term.
    action: ACCEPT
    reason: >-
      Duplicate of the well-supported core biological process; CYP11A1 initiates
      C21-steroid hormone biosynthesis by producing pregnenolone.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        the precursor to all steroid hormones, pregnenolone, is synthesized from
        cholesterol
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Combined-IEA (RHEA/EC 1.14.15.6) mapping to the core cholesterol monooxygenase
      (side-chain-cleaving) activity.
    action: ACCEPT
    reason: >-
      EC 1.14.15.6 corresponds exactly to the cholesterol side-chain cleavage activity of
      CYP11A1; this reinforces the core molecular function annotation.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'EC=1.14.15.6'
- term:
    id: GO:0008395
    label: steroid hydroxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        Catalyzes three sequential oxidation reactions of cholesterol, namely the
        hydroxylation
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA (IEA) annotation to sterol metabolic process, a correct broad parent of
      cholesterol metabolic process.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'PATHWAY: Steroid metabolism; cholesterol metabolism.'
- term:
    id: GO:0016705
    label: oxidoreductase activity, acting on paired donors, with incorporation or
      reduction of molecular oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IEA) mapping to a high-level P450 oxidoreductase parent term. Correct
      but generic.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase that catalyzes the side-chain
- term:
    id: GO:0016713
    label: 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
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of
        CYP11A1
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Combined-IEA annotation for heme binding, the essential cofactor of this
      heme-thiolate cytochrome P450.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'COFACTOR:'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25464930
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:25464930
      supporting_text: >-
        The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA,
        ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated
- term:
    id: GO:0120178
    label: steroid hormone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:21636783
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation to steroid hormone biosynthetic process,
      supported by the structural/biochemical characterization of pregnenolone
      biosynthesis by the CYP11A1-adrenodoxin complex.
    action: ACCEPT
    reason: >-
      CYP11A1 produces pregnenolone, the precursor of all steroid hormones, thereby
      initiating steroid hormone biosynthesis. This is a core biological process for the
      gene.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        the precursor to all steroid hormones, pregnenolone, is synthesized from
        cholesterol
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-196108
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS annotation (Pregnenolone biosynthesis) to C21-steroid hormone
      biosynthesis, consistent with the well-supported core biological process.
    action: ACCEPT
    reason: >-
      Reactome documents CYP11A1 as the enzyme converting cholesterol to pregnenolone in
      the inner mitochondrial membrane, the entry step of C21-steroid hormone
      biosynthesis.
    supported_by:
    - reference_id: Reactome:R-HSA-196108
      supporting_text: >-
        cholesterol is converted to pregnenolone in a sequence of three reactions, all
        catalyzed by CYP11A (side chain cleavage enzyme)
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-211976
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS annotation (Endogenous sterols) to sterol metabolic process. Correct
      broad parent capturing the enzyme's role in cholesterol/sterol homeostasis.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: Reactome:R-HSA-211976
      supporting_text: >-
        A number of CYPs take part in cholesterol biosynthesis and elimination, thus
        playing an important role in maintaining cholesterol homeostasis
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway (IEA) mapping to cholesterol metabolic process, consistent with the
      IBA/IDA/ISS annotations to the same term.
    action: ACCEPT
    reason: >-
      Cholesterol is the CYP11A1 substrate; its metabolism is a core process. Duplicate
      of the experimentally-supported cholesterol metabolic process annotation.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'PATHWAY: Steroid metabolism; cholesterol metabolism.'
- term:
    id: GO:0008207
    label: C21-steroid hormone metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway (IEA) mapping to C21-steroid hormone metabolic process, the metabolic
      parent of the C21-steroid hormone biosynthetic process.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'PATHWAY: Lipid metabolism; C21-steroid hormone metabolism.'
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193054
  qualifier: enables
  review:
    summary: >-
      Reactome TAS annotation for the first hydroxylation step (cholesterol to
      22beta-hydroxycholesterol) catalyzed by CYP11A1, supporting the core cholesterol
      side-chain-cleaving activity.
    action: ACCEPT
    reason: >-
      Reactome documents this as the first of the three CYP11A1-catalyzed reactions of
      the side-chain cleavage sequence; supports the core molecular function.
    supported_by:
    - reference_id: Reactome:R-HSA-193054
      supporting_text: >-
        Cholesterol and NADPH + H+ react to form 22beta-hydroxycholesterol, NADP+, and
        H2O, catalyzed by CYP11A (P450scc)
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193065
  qualifier: enables
  review:
    summary: >-
      Reactome TAS annotation for the second hydroxylation step (22beta-hydroxycholesterol
      to 20alpha,22beta-hydroxycholesterol) catalyzed by CYP11A1.
    action: ACCEPT
    reason: >-
      Documents the second CYP11A1-catalyzed reaction of the side-chain cleavage sequence;
      supports the core molecular function.
    supported_by:
    - reference_id: Reactome:R-HSA-193065
      supporting_text: >-
        22beta-hydroxycholesterol, NADPH + H+, and O2 react to form
        20alpha,22beta-hydroxycholesterol, NADP+ and H2O, catalyzed by CYP11A (P450scc)
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193101
  qualifier: enables
  review:
    summary: >-
      Reactome TAS annotation for the final C20-C22 bond cleavage step
      (20alpha,22beta-dihydroxycholesterol to pregnenolone) catalyzed by CYP11A1.
    action: ACCEPT
    reason: >-
      Documents the C-C bond scission that completes side-chain cleavage to pregnenolone;
      supports the core molecular function.
    supported_by:
    - reference_id: Reactome:R-HSA-193101
      supporting_text: >-
        This cleavage reaction is catalysed by CYP11A (P450scc) associated with the inner
        mitochondrial membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) localization to the mitochondrial inner membrane,
      transferred from an ortholog. Consistent with the IBA/IEA annotations.
    action: ACCEPT
    reason: >-
      Corroborates the core mitochondrial inner membrane localization of CYP11A1.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Mitochondrion inner membrane
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        defined a
        mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5580269
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: Localizes to the matrix side of the mitochondrion inner membrane.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193054
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to the mitochondrial matrix, associated with the first
      side-chain cleavage reaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the matrix-facing orientation of the inner-membrane-associated enzyme;
      retain as non-core relative to the primary inner membrane localization.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: Localizes to the matrix side of the mitochondrion inner membrane.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193065
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to the mitochondrial matrix, associated with the second
      side-chain cleavage reaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the matrix-facing orientation of the inner-membrane-associated enzyme;
      retain as non-core relative to the primary inner membrane localization.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: Localizes to the matrix side of the mitochondrion inner membrane.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193101
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localization to the mitochondrial matrix, associated with the final
      C-C cleavage step; the product pregnenolone is released into the matrix.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: Reactome:R-HSA-193101
      supporting_text: >-
        PREG is substantially more hydrophilic than cholesterol (CHOL) and
        hydroxycholesterol (HCHOL) and is released into the mitochondrial matrix
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity (ISS) annotation to cholesterol metabolic process, transferred
      from a characterized ortholog. Consistent with the core role.
    action: ACCEPT
    reason: >-
      Corroborates the core cholesterol metabolic process annotation; cholesterol is the
      direct substrate of CYP11A1.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: 'PATHWAY: Steroid metabolism; cholesterol metabolism.'
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Sequence-similarity (ISS) annotation to the core cholesterol monooxygenase
      (side-chain-cleaving) activity, transferred from a characterized ortholog.
    action: ACCEPT
    reason: >-
      Corroborates the diagnostic core molecular function of CYP11A1.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: A cytochrome P450 monooxygenase that catalyzes the side-chain
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:21636783
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      The study resolved the CYP11A1 reaction sequence converting cholesterol to
      pregnenolone (a C21 steroid), directly evidencing its role in C21-steroid hormone
      biosynthesis.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        the precursor to all steroid hormones, pregnenolone, is synthesized from
        cholesterol
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IDA
  original_reference_id: PMID:21636783
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental (IDA) annotation to cholesterol metabolic process, from the
      structural/biochemical characterization of CYP11A1 acting on cholesterol.
    action: ACCEPT
    reason: >-
      Cholesterol is the direct substrate whose side chain is cleaved by CYP11A1; the
      study characterized this reaction, evidencing a core cholesterol metabolic role.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        the precursor to all steroid hormones, pregnenolone, is synthesized from
        cholesterol
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: IDA
  original_reference_id: PMID:21636783
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        allow us to define the mechanism underlying sequential hydroxylations of the
        cholesterol and suggest the mechanism of C-C bond cleavage
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IDA
  original_reference_id: PMID:21636783
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) annotation to heme binding, from the crystal structure
      resolving the heme iron of CYP11A1 in the redox complex with adrenodoxin.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:21636783
      supporting_text: >-
        the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of
        CYP11A1
- term:
    id: GO:0042359
    label: vitamin D metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: DrugBank; DB00169; Cholecalciferol.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity (ISS) localization to the mitochondrion, transferred from an
      ortholog. Correct but broader than the mitochondrial inner membrane localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment but broader than the specific mitochondrial inner membrane
      annotation; retain as non-core parent.
    supported_by:
    - reference_id: file:human/CYP11A1/CYP11A1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Mitochondrion inner membrane
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11502818
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11502818
      supporting_text: >-
        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
- term:
    id: GO:0006700
    label: C21-steroid hormone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18182448
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Functional studies of patient mutations quantified residual P450scc activity
      (L141W 38%, V415E 0%), directly linking CYP11A1 enzymatic activity to C21-steroid
      hormone biosynthesis.
    supported_by:
    - reference_id: PMID:18182448
      supporting_text: >-
        Mitochondrial cytochrome P450scc converts cholesterol to pregnenolone
        in all steroidogenic tissues
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IMP
  original_reference_id: PMID:18182448
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype (IMP) annotation to cholesterol metabolic process, based on
      functional characterization of CYP11A1 loss-of-function mutations impairing
      cholesterol conversion.
    action: ACCEPT
    reason: >-
      Patient mutations with reduced/absent P450scc activity impair conversion of
      cholesterol to pregnenolone, evidencing CYP11A1's role in cholesterol metabolism.
    supported_by:
    - reference_id: PMID:18182448
      supporting_text: >-
        One patient harbored the novel P450scc missense mutations L141W and V415E, which
        retained 38 and 0% activity, respectively
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: IDA
  original_reference_id: PMID:11502818
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) annotation to the core cholesterol side-chain-cleaving
      activity, from functional assay of the patient's CYP11A1 mutation.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11502818
      supporting_text: >-
        inserted into a catalytically active fusion protein of the P450scc system
        (H2N-P450scc-Adrenodoxin Reductase-Adrenodoxin-COOH), completely inactivating
        enzymatic activity
- term:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  evidence_type: IDA
  original_reference_id: PMID:18182448
  qualifier: enables
  review:
    summary: >-
      Direct experimental (IDA) annotation to the core cholesterol side-chain-cleaving
      activity, quantifying residual activity of patient CYP11A1 mutants.
    action: ACCEPT
    reason: >-
      Functional studies directly measured P450scc catalytic activity of patient mutants
      (L141W 38%, V415E 0%), evidencing the cholesterol side-chain-cleaving monooxygenase
      function.
    supported_by:
    - reference_id: PMID:18182448
      supporting_text: >-
        One patient harbored the novel P450scc missense mutations L141W and V415E, which
        retained 38 and 0% activity, respectively
core_functions:
- description: >-
    Cholesterol side-chain cleavage monooxygenase (P450scc): catalyzes the first and
    rate-limiting enzymatic step of steroidogenesis, converting cholesterol to
    pregnenolone through three sequential mono-oxygenations at the matrix face of the
    mitochondrial inner membrane, using electrons delivered by the ferredoxin (adrenodoxin)
    system.
  molecular_function:
    id: GO:0008386
    label: cholesterol monooxygenase (side-chain-cleaving) activity
  directly_involved_in:
  - id: GO:0006694
    label: steroid biosynthetic process
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:21636783
    supporting_text: >-
      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)
- description: >-
    Heme binding: CYP11A1 binds a b-type heme via an axial cysteine thiolate (Cys462),
    the essential cofactor for its cytochrome P450 monooxygenase chemistry.
  molecular_function:
    id: GO:0020037
    label: heme binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:21636783
    supporting_text: >-
      the [2Fe-2S] cluster of Adx is positioned 17.4 Å away from the heme iron of CYP11A1
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/CYP11A1/CYP11A1-uniprot.txt
  title: UniProtKB entry P05108 (CP11A_HUMAN), Cholesterol side-chain cleavage enzyme,
    mitochondrial
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt record for CYP11A1/P450scc; source for FUNCTION, CATALYTIC ACTIVITY,
      COFACTOR (heme), SUBCELLULAR LOCATION (mitochondrion inner membrane), and disease.
- id: PMID:11502818
  title: Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc)
    gene in a patient with 46,XY sex reversal and adrenal insufficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Case report + functional assay; establishes CYP11A1 as the sole enzyme converting
      cholesterol to pregnenolone and links loss-of-function to adrenal insufficiency /
      46,XY sex reversal.
- id: PMID:18182448
  title: Severe combined adrenal and gonadal deficiency caused by novel mutations
    in the cholesterol side chain cleavage enzyme, P450scc.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Functional characterization of novel CYP11A1 mutations (L141W 38% activity, V415E
      0%); supports the side-chain-cleaving activity and steroid biosynthesis role.
- id: PMID:21636783
  title: Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase
    system.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structure of the CYP11A1-adrenodoxin complex with substrate/intermediates;
      defines heme iron, electron transfer, and the sequential cholesterol side-chain
      cleavage mechanism. Primary support for core molecular function.
- id: PMID:25464930
  title: 'Novel interactive partners of neuroligin 3: new aspects for pathogenesis
    of autism.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Y2H screen for NLGN3 interactors validated a CYP11A1-NLGN3 interaction; the sole
      basis for the bare protein binding (GO:0005515) IPI. Not connected to CYP11A1's
      steroidogenic function.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-confidence human mitochondrial proteome (MitoCoP); source of the HTP
      mitochondrion localization annotation.
- id: Reactome:R-HSA-193054
  title: Oxidation of cholesterol to 22beta-hydroxycholesterol
  findings: []
- id: Reactome:R-HSA-193065
  title: Oxidation of 22beta-hydroxycholesterol to 20alpha,22beta-hydroxycholesterol
  findings: []
- id: Reactome:R-HSA-193101
  title: CYP11A1 cleaves 20a,22b-DHCHOL
  findings: []
- id: Reactome:R-HSA-196108
  title: Pregnenolone biosynthesis
  findings: []
- id: Reactome:R-HSA-211976
  title: Endogenous sterols
  findings: []
- id: Reactome:R-HSA-5580269
  title: Defective CYP11A1 does not cleave 20a,22b-DHCHOL
  findings: []
proposed_new_terms: []
suggested_questions:
- question: >-
    What is the physiological significance of CYP11A1 vitamin D3 /
    7-dehydrocholesterol metabolism (secosteroid production) relative to its canonical
    steroidogenic role?
- question: >-
    Is the CYP11A1-NLGN3 interaction reported in the yeast two-hybrid screen
    physiologically relevant, or an artifact of the screen?
suggested_experiments:
- description: >-
    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.
  experiment_type: metabolomics