CYP7B1 (cytochrome P450 7B1) is an oxysterol 7-alpha-hydroxylase, a heme/iron cytochrome P450 monooxygenase anchored in the endoplasmic reticulum membrane. It catalyzes the 7-alpha-hydroxylation of oxysterols, chiefly 25-hydroxycholesterol and 27-hydroxycholesterol ((25R)-cholest-5-ene-3beta,26-diol), as well as 24S-hydroxycholesterol, using molecular oxygen with electrons from NADPH via cytochrome P450 reductase. This is the committed 7-alpha-hydroxylation step of the acidic (alternative) bile-acid biosynthesis pathway, converting oxysterols generated by CH25H, CYP27A1 and CYP46A1 into 7-alpha-hydroxylated intermediates that are transported to the liver and converted to bile acids. CYP7B1 also 7-alpha-hydroxylates 3-hydroxy steroids and neurosteroids such as dehydroepiandrosterone (DHEA) and pregnenolone, contributing to neurosteroid metabolism, and its product 7-alpha,25-dihydroxycholesterol is the ligand for the chemotactic receptor GPR183/EBI2 that guides B-cell migration. The enzyme is widely expressed (brain, testis, ovary, prostate, liver, intestine, kidney). Loss-of-function variants cause hereditary spastic paraplegia type 5A (SPG5A), a progressive motor-neuron degeneration associated with oxysterol accumulation, and, in severe biallelic cases, congenital bile acid synthesis defect type 3 (CBAS3) with neonatal cholestasis and liver failure.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008395 steroid hydroxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA phylogenetic call that CYP7B1 has steroid hydroxylase activity. This is correct but a broad parent of the specific oxysterol/steroid 7-alpha-hydroxylase activity that is directly demonstrated. Keep as a correct-but-general MF. Reason: CYP7B1 hydroxylates a range of steroids and oxysterols at the 7-alpha (and minor 6-alpha) position, so steroid hydroxylase activity is accurate. The more informative core MF is captured separately by oxysterol 7-alpha-hydroxylase activity (GO:0008396) and the specific 25-/24S-hydroxycholesterol 7-alpha-hydroxylase terms. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt Catalyzes the hydroxylation of carbon hydrogen bonds of steroids with a preference for 7-alpha position |
| GO:0006699 bile acid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA call that CYP7B1 participates in bile acid biosynthesis. This is the core biological process: CYP7B1 catalyzes the committed 7-alpha-hydroxylation step of the acidic (alternative) bile-acid pathway. Reason: Directly supported by experimental human data: oxysterol 7-alpha-hydroxylase is active in the acidic pathway for bile acid synthesis, and loss of activity causes an inborn error of bile acid synthesis (CBAS3). Supporting Evidence: PMID:9802883 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis |
| GO:0042632 cholesterol homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA call linking CYP7B1 to cholesterol homeostasis. By clearing oxysterols (oxygenated cholesterol derivatives) into the bile-acid pathway, CYP7B1 contributes to cholesterol/oxysterol turnover; defective function causes cholesterol/oxysterol dysregulation implicated in SPG5A. Keep as a non-core downstream/physiological role. Reason: The direct molecular activity is oxysterol 7-alpha-hydroxylation; cholesterol homeostasis is a broader physiological consequence rather than the enzyme's specific function. SPG5A studies frame CYP7B1 loss as defective cholesterol homeostasis, supporting the association but as a downstream role. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA assigning monooxygenase activity from cytochrome P450 domains. Correct P450 chemistry; a broad parent of the specific 7-alpha-hydroxylase activity. Reason: CYP7B1 is a cytochrome P450 monooxygenase that inserts one oxygen atom into the substrate and reduces the other to water, consistent with monooxygenase activity. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA for iron ion binding, reflecting the heme iron of the P450 catalytic center (axial Cys449 ligand to heme Fe). Correct and supported. Reason: CYP7B1 uses a heme cofactor whose iron is essential for oxygen activation; the heme axial binding residue is annotated at position 449, confirming iron coordination. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt BINDING 449 /ligand="heme" /ligand_part="Fe" |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular-location mapping placing CYP7B1 in the endoplasmic reticulum (microsomal) membrane. This is the correct, core localization for this multi-pass membrane P450. Reason: Experimentally established microsomal/ER-membrane localization; the enzyme has two predicted transmembrane helices and hepatic microsomal oxysterol 7-alpha-hydroxylase activity is the assayed activity. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0008202 steroid metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning IEA for steroid metabolic process. Correct but a broad parent; CYP7B1's steroid role is specifically 7-alpha-hydroxylation of 3-hydroxy steroids/neurosteroids (DHEA, pregnenolone) feeding steroid hormone biosynthesis. Reason: CYP7B1 metabolizes steroids and neurosteroids; steroid metabolic process is accurate at a general level and is consistent with the UniProt steroid hormone biosynthesis pathway annotation. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt A cytochrome P450 monooxygenase involved in the metabolism of endogenous oxysterols and steroid hormones, including neurosteroids |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA capturing the P450 oxidoreductase mechanism (paired-donor monooxygenase using O2). Correct broad MF parent of the hydroxylase activity. Reason: CYP7B1 uses molecular oxygen, incorporating one oxygen atom into substrate and reducing the other to water with electrons from NADPH-cytochrome P450 reductase, exactly the chemistry described by this term. Supporting Evidence: file:human/CYP7B1/CYP7B1-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 |
| GO:0020037 heme binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA for heme binding, reflecting the P450 heme cofactor. Correct and supported by the annotated heme axial ligand. Reason: CYP7B1 requires heme as cofactor (ChEBI:CHEBI:30413) coordinated via Cys449; heme binding is a core molecular function of this cytochrome P450. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt COFACTOR: Name=heme |
| GO:0033782 24S-hydroxycholesterol 7-alpha-hydroxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated IEA (RHEA/EC 1.14.14.26) for 24S-hydroxycholesterol 7-alpha-hydroxylase activity. Consistent with the UniProt catalytic-activity annotation for the (24S)-hydroxycholesterol reaction; a specific, correct MF (the human activity here is by similarity to mouse). Reason: UniProt records the (24S)-hydroxycholesterol -> (24S)-7alpha-dihydroxycholesterol reaction (EC 1.14.14.26), matching this specific hydroxylase activity. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt 24-hydroxycholesterol 7-alpha-hydroxylase |
| GO:0033783 25-hydroxycholesterol 7-alpha-hydroxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated IEA (RHEA/EC 1.14.14.29) for 25-hydroxycholesterol 7-alpha-hydroxylase activity. This is a specific, experimentally supported activity (see EXP annotations from PMID:10588945 and PMID:9802883). Reason: The 25-hydroxycholesterol -> 7alpha,25-dihydroxycholesterol reaction (EC 1.14.14.29) is directly demonstrated for human CYP7B1 and is a component of the enzyme's oxysterol 7-alpha-hydroxylase core function. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt Reaction=25-hydroxycholesterol + reduced [NADPH--hemoprotein reductase] + O2 = 7alpha,25-dihydroxycholesterol |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput affinity-capture/mass-spec interactome (BioPlex) annotation of CYP7B1 binding ubiquitin (UBB/UBC, P0CG47). Bare protein binding to a near-universal interactor is uninformative about CYP7B1's molecular function. Reason: GO:0005515 "protein binding" with a single, non-specific partner (ubiquitin) from a proteome-scale screen conveys no functional insight and is discouraged per curation guidance; it is not wrong but is an over-annotation. Retained rather than removed because it is an experimental IPI. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Second BioPlex proteome-scale interactome annotation of CYP7B1 binding ubiquitin (UBB/UBC, P0CG47). As above, an uninformative bare protein-binding interaction. Reason: Same rationale as the companion BioPlex annotation: high-throughput protein binding to ubiquitin does not inform CYP7B1's molecular function and is an over-annotation, but is kept because it is an experimental IPI. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome |
| GO:0006699 bile acid biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated IEA (UniPathway UPA00221 / mouse ortholog Q60991) for bile acid biosynthetic process. Correct and redundant with the experimentally supported core BP annotation. Reason: CYP7B1 catalyzes the committed 7-alpha-hydroxylation step of the acidic bile-acid pathway; UniProt assigns the lipid metabolism; bile acid biosynthesis pathway. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt PATHWAY: Lipid metabolism; bile acid biosynthesis |
| GO:0035754 B cell chemotaxis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transferred from the mouse ortholog (Q60991): CYP7B1 indirectly promotes B-cell chemotaxis because its product 7-alpha,25-dihydroxycholesterol is the ligand for GPR183/EBI2 that guides B-cell positioning. A real but non-core, indirect/downstream role in human. Reason: This is a physiological consequence of the enzyme's oxysterol product acting as an EBI2 ligand, not a direct molecular function of CYP7B1; the human evidence is by similarity to mouse. Keep as non-core. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt regulates B cell migration in germinal centers of lymphoid organs |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-192105 | ACCEPT | Summary: Reactome TAS (Synthesis of bile acids and bile salts) for bile acid biosynthetic process. Consistent with the core biological role of CYP7B1. Reason: Reactome places CYP7B1 in bile acid/bile salt synthesis, matching the experimentally established acidic-pathway 7-alpha-hydroxylation role. Supporting Evidence: PMID:9802883 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193807 | ACCEPT | Summary: Reactome TAS (Synthesis of bile acids and bile salts via 27-hydroxycholesterol) for bile acid biosynthetic process. This is precisely the acidic pathway in which CYP7B1 7-alpha-hydroxylates 27-hydroxycholesterol. Reason: CYP7B1 7-alpha-hydroxylates 27-hydroxycholesterol ((25R)-cholest-5-ene-3beta,26-diol), the defining step of the 27-hydroxycholesterol (acidic) route to bile acids. Supporting Evidence: PMID:10588945 able to catalyze 7alpha-hydroxylation of 27-hydroxycholesterol and |
| GO:0016125 sterol metabolic process | TAS Reactome:R-HSA-211976 | ACCEPT | Summary: Reactome TAS (Endogenous sterols) for sterol metabolic process. CYP7B1 metabolizes oxysterols (oxygenated sterols), so this broad BP is correct. Reason: By 7-alpha-hydroxylating oxysterols such as 25- and 27-hydroxycholesterol, CYP7B1 participates in endogenous sterol metabolism; a correct, somewhat broad biological-process term. Supporting Evidence: PMID:10588945 Oxysterol 7alpha-hydroxylase has broad substrate specificity for sterol metabolites |
| GO:0008396 oxysterol 7-alpha-hydroxylase activity | TAS Reactome:R-HSA-191972 | ACCEPT | Summary: Reactome TAS (27-hydroxycholesterol is 7alpha-hydroxylated) for oxysterol 7-alpha-hydroxylase activity. This is the specific, core molecular function of CYP7B1. Reason: Oxysterol 7-alpha-hydroxylase activity is the defining catalytic function, experimentally demonstrated for 27-hydroxycholesterol and other oxysterols; the best-fit specific MF term. Supporting Evidence: PMID:10588945 able to catalyze 7alpha-hydroxylation of 27-hydroxycholesterol and |
| GO:0008396 oxysterol 7-alpha-hydroxylase activity | TAS Reactome:R-HSA-192065 | ACCEPT | Summary: Reactome TAS (CYP7B1 7-hydroxylates 25OH-CHOL) for oxysterol 7-alpha-hydroxylase activity. Specific, core MF; consistent with the experimental 25-hydroxycholesterol activity. Reason: CYP7B1 7-alpha-hydroxylates 25-hydroxycholesterol, an oxysterol; oxysterol 7-alpha-hydroxylase activity is the correct specific MF. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt Reaction=25-hydroxycholesterol + reduced [NADPH--hemoprotein reductase] + O2 = 7alpha,25-dihydroxycholesterol |
| GO:0008396 oxysterol 7-alpha-hydroxylase activity | TAS Reactome:R-HSA-5602885 | ACCEPT | Summary: Reactome TAS (Defective CYP7B1 does not 7-hydroxylate 25OH-CHOL) for oxysterol 7-alpha-hydroxylase activity, framed around the disease (SPG5A/CBAS3) loss of activity. Correct specific core MF. Reason: The disease reaction confirms the wild-type activity: CYP7B1 normally 7-alpha-hydroxylates 25-hydroxycholesterol; its loss underlies CBAS3/SPG5A. Supporting Evidence: PMID:9802883 Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the |
| GO:0033782 24S-hydroxycholesterol 7-alpha-hydroxylase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from the mouse ortholog (Q60991) for 24S-hydroxycholesterol 7-alpha-hydroxylase activity. Consistent with the UniProt catalytic-activity record (by similarity) for the (24S)-hydroxycholesterol reaction; a specific, plausible MF. Reason: The (24S)-hydroxycholesterol -> (24S)-7alpha-dihydroxycholesterol reaction is annotated for CYP7B1 by similarity to the mouse ortholog; a component of its oxysterol 7-alpha-hydroxylase activity. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt Reaction=(24S)-hydroxycholesterol + reduced [NADPH--hemoprotein reductase] + O2 |
| GO:0033783 25-hydroxycholesterol 7-alpha-hydroxylase activity | EXP PMID:10588945 Structure and functions of human oxysterol 7alpha-hydroxylas... | ACCEPT | Summary: Experimental (EXP) demonstration that recombinant human CYP7B1 7-alpha-hydroxylates oxysterols. This is a core, directly measured molecular function. Reason: Human CYP7B1 transiently expressed in 293/T cells catalyzed 7-alpha-hydroxylation of 27-hydroxycholesterol and DHEA, directly demonstrating oxysterol/steroid 7-alpha-hydroxylase activity (the 25-hydroxycholesterol activity is the closely related specific term). Supporting Evidence: PMID:10588945 able to catalyze 7alpha-hydroxylation of 27-hydroxycholesterol and |
| GO:0033783 25-hydroxycholesterol 7-alpha-hydroxylase activity | EXP PMID:9802883 Identification of a new inborn error in bile acid synthesis:... | ACCEPT | Summary: Experimental (EXP) support: patient hepatic microsomal oxysterol 7-alpha-hydroxylase activity was undetectable and the mutant (R388X) protein was inactive when expressed, confirming CYP7B1 as the 7-alpha-hydroxylase of oxysterols including 25-hydroxycholesterol. Reason: Loss of the 25/27-hydroxycholesterol 7-alpha-hydroxylase activity in a CYP7B1 loss-of-function patient (with >4,500-fold accumulation of 27-hydroxycholesterol) demonstrates this catalytic activity for human CYP7B1. Supporting Evidence: PMID:9802883 truncated protein was inactive when expressed in 293 cells |
| GO:0035754 B cell chemotaxis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from the mouse ortholog (Q60991) for B-cell chemotaxis, via the CYP7B1 product 7-alpha,25-dihydroxycholesterol acting as the EBI2/GPR183 ligand. Real but indirect and non-core in human. Reason: As with the Ensembl IEA, this reflects an indirect downstream role mediated by an oxysterol product rather than CYP7B1's direct molecular function; keep as non-core. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt regulates B cell migration in germinal centers of lymphoid organs |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5602885 | ACCEPT | Summary: Reactome TAS for endoplasmic reticulum membrane localization. Correct, core localization for this microsomal P450. Reason: CYP7B1 is a multi-pass ER/microsomal membrane protein; hepatic microsomal oxysterol 7-alpha-hydroxylase activity is the assayed activity. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-191972 | ACCEPT | Summary: Reactome TAS for ER membrane localization (duplicate of the core CC annotation). Correct. Reason: Consistent with the established microsomal/ER-membrane localization of CYP7B1. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt Microsome membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-192065 | ACCEPT | Summary: Reactome TAS for ER membrane localization (duplicate of the core CC annotation). Correct. Reason: Consistent with the established microsomal/ER-membrane localization of CYP7B1. Supporting Evidence: file:human/CYP7B1/CYP7B1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0006699 bile acid biosynthetic process | TAS PMID:9802883 Identification of a new inborn error in bile acid synthesis:... | ACCEPT | Summary: TAS (from the primary CBAS3 paper) for bile acid biosynthetic process. Core biological role, directly supported by the human inborn-error phenotype. Reason: Setchell et al. defined a new inborn error of bile acid synthesis caused by oxysterol 7-alpha-hydroxylase deficiency, placing CYP7B1 in the acidic bile acid biosynthesis pathway. Supporting Evidence: PMID:9802883 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis |
| GO:0008396 oxysterol 7-alpha-hydroxylase activity | TAS PMID:9802883 Identification of a new inborn error in bile acid synthesis:... | ACCEPT | Summary: TAS (from the primary CBAS3 paper) for oxysterol 7-alpha-hydroxylase activity. This is the specific, core molecular function of CYP7B1. Reason: The paper identifies CYP7B1 as the microsomal oxysterol 7-alpha-hydroxylase whose deficiency causes accumulation of 27-hydroxycholesterol and severe neonatal liver disease. Supporting Evidence: PMID:9802883 7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol |
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