CYP39A1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0008395 steroid hydroxylase activity	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Correct but general parent term. CYP39A1 is a steroid (sterol) hydroxylase acting on the oxysterol (24S)-hydroxycholesterol. This IBA family-level call is a true ancestor of the specific activity GO:0033782, so it is not wrong, but a more specific term is available and experimentally supported. Reason: Correct broad ancestor, but subsumed by the experimentally supported specific term GO:0033782 (24S-hydroxycholesterol 7-alpha-hydroxylase activity). Retained as a valid parent but flagged as over-general. Propagation Review Root cause: TERM SCOPING PROBLEM
GO:0006699 bile acid biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Correct core biological process. CYP39A1 acts in the alternative bile-acid synthesis pathway, 7-alpha-hydroxylating 24-hydroxycholesterol en route to bile acids in the liver. This IBA call agrees with the experimental IDA (PMID:10748047) and UniProt PATHWAY annotation. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt Catalyzes 7-alpha hydroxylation of (24S)- hydroxycholesterol, a neural oxysterol that is metabolized to bile acids in the liver
GO:0042632 cholesterol homeostasis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Plausible higher-level physiological role: by converting brain-derived 24-hydroxycholesterol to bile acids, CYP39A1 contributes to whole-body cholesterol elimination. This is a general downstream process rather than the enzyme's direct catalytic role, so it is retained as non-core. Reason: A downstream/indirect physiological outcome of the catalytic step, not the specific molecular activity; keep as non-core context.
GO:0004497 monooxygenase activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Correct but very general MF. CYP39A1 is a P450 monooxygenase; UniProt describes the classic mechanism of inserting one oxygen atom into the substrate. This InterPro-based parent is subsumed by the specific activity GO:0033782. Reason: Correct mechanistic superclass but subsumed by the specific, experimentally supported GO:0033782. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule
GO:0005506 iron ion binding	IEA GO_REF:0000002	ACCEPT	Summary: Correct. As a cytochrome P450, CYP39A1 binds heme via an axial iron ligand; UniProt annotates the heme-Fe axial binding residue at position 414. This InterPro-based iron ion binding call is accurate and mechanistically essential. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt axial binding residue
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Correct core localization. CYP39A1 is a microsomal, multi-pass ER membrane protein, consistent with UniProt SUBCELLULAR LOCATION and the original description of a microsomal P450. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0007586 digestion	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Over-broad, indirect process. Bile acids ultimately aid lipid digestion, but CYP39A1's molecular role is a hepatic oxysterol hydroxylation step in the minor alternative bile-acid pathway (chiefly for brain cholesterol disposal), not digestion per se. This ARBA electronic call is an over-annotation. Reason: Downstream physiological consequence of bile-acid production, not this enzyme's function; the alternative pathway is a minor bile-acid source focused on cholesterol clearance.
GO:0008387 steroid 7-alpha-hydroxylase activity	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Correct but general parent. GO:0008387 is the direct parent of the specific activity GO:0033782 (24S-hydroxycholesterol 7-alpha-hydroxylase). CYP39A1 is a steroid 7-alpha-hydroxylase, so this ARBA call is accurate but subsumed by the more specific, experimentally supported term. Reason: Accurate parent term but subsumed by GO:0033782; retained as a valid but over-general ancestor.
GO:0016125 sterol metabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Correct but general BP. CYP39A1 metabolizes the sterol/oxysterol 24-hydroxycholesterol; this ARBA call is a true ancestor of the more specific bile acid biosynthetic / cholesterol catabolic processes. Reason: Correct broad ancestor of the specific bile-acid/cholesterol-catabolic processes; keep as non-core context.
GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Correct but very general MF, the mechanistic superclass of P450 monooxygenase activity. UniProt describes the paired-donor O2 chemistry (one O into substrate, the other reduced to water with NADPH-derived electrons). Subsumed by the specific term GO:0033782. Reason: Correct mechanistic superclass but subsumed by the specific GO:0033782. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase
GO:0020037 heme binding	IEA GO_REF:0000002	ACCEPT	Summary: Correct. CYP39A1 uses a heme cofactor (ChEBI:CHEBI:30413) with an axial Fe-coordinating residue at position 414, as annotated in UniProt. Heme binding is essential to its P450 monooxygenase activity. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt Name=heme; Xref=ChEBI:CHEBI:30413
GO:0033782 24S-hydroxycholesterol 7-alpha-hydroxylase activity	IEA GO_REF:0000120	ACCEPT	Summary: Correct and the precise core molecular function. This EC/Rhea-based electronic call (EC 1.14.14.26, RHEA:46124) matches the UniProt RecName and is duplicated by the EXP annotation from PMID:25201972. This is the defining activity of CYP39A1. Supporting Evidence: PMID:10748047 CYP39A1 is a microsomal cytochrome P450 enzyme that has preference for 24-hydroxycholesterol Reactome:R-HSA-192178 7-alpha-hydroxylates 24-hydroxycholesterol (24OH-CHOL) to cholest-5-ene-3beta,7alpha,24-triol
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a high-throughput interactome study (recording an interaction with HERC3, Q15034). It conveys no specific molecular function and is uninformative for CYP39A1's biology. Retained per policy (not removed) but flagged as an over-annotation. Reason: Uninformative bare protein-binding term from a large-scale interactome screen; no defined functional role. Per policy, IPI protein-binding is kept, not removed.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Second bare "protein binding" IPI (again the HERC3/Q15034 interaction, from a BioPlex-type proteome-scale network). Same rationale as the other IPI: uninformative, retained but over-annotated. Reason: Uninformative bare protein-binding term from a proteome-scale interactome screen; no defined functional role. Per policy, IPI protein-binding is kept, not removed.
GO:0006699 bile acid biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Correct core BP (duplicate of the IBA/IDA/TAS bile-acid biosynthesis annotations). Electronic call via ARBA/ortholog/UniPathway mapping, consistent with the experimentally supported role. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt PATHWAY: Lipid metabolism; bile acid biosynthesis
GO:0006699 bile acid biosynthetic process	TAS Reactome:R-HSA-193775	ACCEPT	Summary: Correct core BP, curated by Reactome as the pathway "Synthesis of bile acids and bile salts via 24-hydroxycholesterol," in which CYP39A1 performs the initiating 7-alpha-hydroxylation. Consistent with experimental evidence. Supporting Evidence: Reactome:R-HSA-193775 24-hydroxycholesterol is synthesized in the brain, exported to the liver, and converted there to bile acids and bile salts
GO:0016125 sterol metabolic process	TAS Reactome:R-HSA-211976	KEEP AS NON CORE	Summary: Correct but general BP, curated by Reactome ("Endogenous sterols") for P450s that participate in cholesterol/sterol metabolism and homeostasis. A true ancestor of the specific bile-acid/cholesterol-catabolic processes; kept 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:0006707 cholesterol catabolic process	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: Correct BP. Conversion of the cholesterol-derived oxysterol 24-hydroxycholesterol to bile acids is a cholesterol catabolic/degradation route; UniProt annotates the PATHWAY "Steroid metabolism; cholesterol degradation." Closely parallels bile acid biosynthesis; kept as non-core. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt PATHWAY: Steroid metabolism; cholesterol degradation
GO:0008396 oxysterol 7-alpha-hydroxylase activity	TAS Reactome:R-HSA-192178	MODIFY	Summary: Correct. CYP39A1 was cloned as a second oxysterol 7alpha-hydroxylase (PMID:10748047), and Reactome curates its 7-alpha-hydroxylation of 24-hydroxycholesterol. This is a valid MF; however, CYP39A1 is specifically selective for 24-hydroxycholesterol, so the more precise GO:0033782 better captures the substrate specificity; modified to it (the gene already carries GO:0033782). Proposed replacements: 24S-hydroxycholesterol 7-alpha-hydroxylase activity Supporting Evidence: PMID:10748047 characterization of murine and human cDNAs and genes that encode a second oxysterol 7alpha-hydroxylase Reactome:R-HSA-192178 7-alpha-hydroxylates 24-hydroxycholesterol (24OH-CHOL) to cholest-5-ene-3beta,7alpha,24-triol
GO:0005789 endoplasmic reticulum membrane	ISS GO_REF:0000024	ACCEPT	Summary: Correct core localization (ISS transfer from the mouse ortholog, Q64654). Consistent with UniProt SUBCELLULAR LOCATION (ER/microsome membrane, multi-pass) and the IEA and Reactome ER-membrane calls. Supporting Evidence: file:human/CYP39A1/CYP39A1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0033782 24S-hydroxycholesterol 7-alpha-hydroxylase activity	EXP PMID:25201972 Genetic, anatomic, and clinical determinants of human serum ...	ACCEPT	Summary: Correct and experimentally supported core molecular function. Biochemical assays of CYP39A1 (and human loss-of-function alleles that elevate serum substrate) establish that the enzyme 7-alpha-hydroxylates 24S-hydroxycholesterol in humans. This is the defining activity of the gene product. Supporting Evidence: PMID:25201972 loss-of-function alleles with additive effects on serum levels of the oxysterol, 24S-hydroxycholesterol, a substrate of the encoded enzyme
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-192178	ACCEPT	Summary: Correct core localization, curated by Reactome for the reaction "CYP39A1 7-hydroxylates 24OH-CHOL," which places the enzyme on the ER membrane. Consistent with the UniProt and ISS calls. Supporting Evidence: Reactome:R-HSA-192178 24-hydroxycholesterol 7-alpha-hydroxylase (CYP39A1), located on the ER membrane
GO:0006699 bile acid biosynthetic process	IDA PMID:10748047 Expression cloning of an oxysterol 7alpha-hydroxylase select...	ACCEPT	Summary: Correct core BP with direct experimental support. The expression-cloning study characterized CYP39A1 as a microsomal, liver-expressed oxysterol 7-alpha-hydroxylase preferring 24-hydroxycholesterol, establishing its role in the bile-acid synthesis pathway. Supporting Evidence: PMID:10748047 CYP39A1 is a microsomal cytochrome P450 enzyme that has preference for 24-hydroxycholesterol and is expressed in the liver
GO:0007586 digestion	TAS PMID:10748047 Expression cloning of an oxysterol 7alpha-hydroxylase select...	MARK AS OVER ANNOTATED	Summary: Over-broad, indirect process. Although bile acids assist fat digestion, the cited paper characterizes CYP39A1 as an oxysterol 7-alpha-hydroxylase in the (minor) alternative bile-acid pathway for cholesterol disposal; "digestion" mischaracterizes this enzyme's specific role. Retained (TAS, not experimental) but flagged as over-annotated. Reason: Downstream/indirect consequence of bile-acid production; the specific role is hepatic oxysterol 7-alpha-hydroxylation, not digestion.
GO:0043231 intracellular membrane-bounded organelle	TAS PMID:10748047 Expression cloning of an oxysterol 7alpha-hydroxylase select...	MARK AS OVER ANNOTATED	Summary: Correct but far too general CC (a broad ancestor of the ER membrane). The specific, well-supported localization is endoplasmic reticulum membrane (GO:0005789). Retained but flagged as over-general. Reason: Very general parent of the ER membrane; subsumed by the specific GO:0005789 localization already annotated.

Gene Description

Existing Annotations Review

Core Functions

24-hydroxycholesterol 7-alpha-hydroxylase: as a microsomal cytochrome P450 monooxygenase, catalyzes the NADPH/O2-dependent 7-alpha-hydroxylation of (24S)-hydroxycholesterol, the committing oxysterol step of the alternative bile-acid synthesis pathway, in the endoplasmic reticulum membrane.

Binds heme as an essential cofactor for its P450 monooxygenase chemistry, coordinating the catalytic iron center that activates molecular oxygen.

Binds the heme iron ion via an axial protein ligand, forming the oxygen-activating catalytic center required for hydroxylation.

References

📚 Additional Documentation

Notes

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