CYP51A1 encodes lanosterol 14-alpha-demethylase (sterol 14-alpha-demethylase; cytochrome P450 51A1; EC 1.14.14.154), a heme-thiolate cytochrome P450 monooxygenase anchored in the endoplasmic reticulum membrane. It catalyzes the first committed post-lanosterol step of cholesterol biosynthesis, the three-step oxidative removal of the 14-alpha-methyl group (C-32) of lanosterol and 24,25-dihydrolanosterol, which is released as formate to yield 4,4-dimethyl-cholesta-dienol intermediates (including follicular-fluid meiosis-activating sterol, FF-MAS). The reaction consumes three molecules of O2 and reducing equivalents delivered by NADPH-cytochrome P450 reductase, and requires a heme cofactor with an axial cysteine-coordinated iron. CYP51 is the most evolutionarily conserved cytochrome P450, present across animals, fungi, and plants; the fungal orthologs are the target of azole antifungal drugs, which also bind human CYP51A1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016491 oxidoreductase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic (IBA) annotation to the generic parent term oxidoreductase activity. CYP51A1 is a cytochrome P450 monooxygenase, so oxidoreductase activity is correct but far less informative than the specific catalytic activity it performs (sterol 14-demethylase activity, GO:0008398). Reason: Correct but overly general; the specific molecular function sterol 14-demethylase activity (GO:0008398) captures the enzyme's activity. Retained as an ancestral/parent term rather than removed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001209376 · sterol 14-alpha demethylase family SUPPORTS TRANSFER Family-level IBA correctly places CYP51A1 as an oxidoreductase, but the child term GO:0008398 is the informative activity for this ortholog. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Cytochrome P450 monooxygenase that catalyzes the CC three-step oxidative removal of the 14alpha-methyl group (C-32) of CC sterols such as lanosterol |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) annotation from cytochrome P450 domain signatures. CYP51A1 is indeed a P450 monooxygenase, verified by structural and biochemical work; this is correct but is a parent of the specific sterol 14-demethylase activity. Reason: Accurate mechanistic class (monooxygenase) but less specific than GO:0008398 sterol 14-demethylase activity; kept as a correct broader term. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Cytochrome P450 monooxygenase that catalyzes the CC three-step oxidative removal of the 14alpha-methyl group (C-32) of CC sterols such as lanosterol |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IEA) annotation for iron binding. CYP51A1 is a heme-thiolate P450; the crystal structure shows a heme iron coordinated by an axial cysteine residue (Cys455), so iron ion binding (as part of the heme cofactor) is correct. Reason: Directly supported by the structure and cofactor assignment; the heme iron is essential to catalysis. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt axial binding residue PMID:20149798 Three crystal structures of human CYP51, ligand-free and complexed with antifungal drugs ketoconazole and econazole |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) subcellular-location annotation. CYP51A1 is an ER-membrane, single-pass membrane protein (microsomal P450), consistent with UniProt subcellular location, Reactome, and the GO-CAM model of cholesterol biosynthesis. Reason: Well-supported localization; ER membrane is the established site of CYP51A1 catalysis in the sterol biosynthetic pathway. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q64654}; Single-pass membrane protein |
| GO:0008398 sterol 14-demethylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) annotation of the core catalytic activity via RHEA/EC mapping (EC 1.14.14.154). This is the defining molecular function of CYP51A1 and is independently supported by experimental annotations. Reason: Core molecular function; correct and specific. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt EC=1.14.14.154 |
| 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) annotation to the P450 mechanistic parent term. Correct as a broad description of the monooxygenase reaction (incorporation of molecular oxygen), but far less specific than sterol 14-demethylase activity (GO:0008398). Reason: Correct mechanistic parent but redundant with the more specific catalytic activity term already annotated. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Cytochrome P450 monooxygenase that catalyzes the CC three-step oxidative removal of the 14alpha-methyl group (C-32) of CC sterols such as lanosterol |
| GO:0020037 heme binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IEA) annotation for heme binding. CYP51A1 is a heme-thiolate P450 with heme as an essential cofactor, confirmed by the crystal structures and the cofactor assignment. Reason: Directly supported; heme is the redox-active prosthetic group required for catalysis. Duplicates the IDA heme-binding annotation from PMID:20149798. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Name=heme; Xref=ChEBI:CHEBI:30413 |
| GO:0042177 negative regulation of protein catabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automated Ensembl-Compara ortholog transfer (IEA) from mouse Cyp51 (UniProtKB:Q8K0C4). This is a downstream/indirect physiological effect attributed to the mouse ortholog, not the enzyme's direct sterol-demethylase function. Reason: An indirect, phenotype-level process transferred electronically from the mouse ortholog; not a direct molecular activity of CYP51A1 and peripheral to its core sterol-biosynthetic role. Duplicated by the ISS annotation below. Not removed because it derives from a curator-anchored mouse annotation, but it should not be treated as core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8K0C4 · Cyp51 (mouse) SUPPORTS SOURCE BUT NOT TARGET Indirect downstream physiology of the mouse ortholog; defensible but not a core molecular activity of human CYP51A1. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:0050709 negative regulation of protein secretion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automated Ensembl-Compara ortholog transfer (IEA) from mouse Cyp51 (UniProtKB:Q8K0C4). An indirect, downstream physiological process, not the direct enzymatic function of CYP51A1. Reason: Indirect phenotype-level process transferred electronically from the mouse ortholog; peripheral to the core sterol-biosynthetic function. Duplicated by the ISS annotation below. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8K0C4 · Cyp51 (mouse) SUPPORTS SOURCE BUT NOT TARGET Indirect downstream physiology of the mouse ortholog; not a core activity of human CYP51A1. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:1900222 negative regulation of amyloid-beta clearance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automated Ensembl-Compara ortholog transfer (IEA) from mouse Cyp51 (UniProtKB:Q8K0C4). A highly indirect neurobiological phenotype linked to sterol/cholesterol homeostasis, not the direct molecular function of the enzyme. Reason: Very indirect, disease/phenotype-level process electronically transferred from the mouse ortholog; not part of the core sterol-biosynthetic function of CYP51A1. Duplicated by the ISS annotation below. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8K0C4 · Cyp51 (mouse) SUPPORTS SOURCE BUT NOT TARGET Very indirect neuro/disease phenotype of the mouse ortholog; not a core molecular activity of human CYP51A1. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-6807047 | ACCEPT | Summary: Reactome TAS annotation placing CYP51A1 in cholesterol biosynthesis (Bloch pathway). CYP51A1 catalyzes the first post-lanosterol demethylation step; this is a core biological process for the gene. Reason: Core biological process; the 14-alpha-demethylation step is an obligatory part of cholesterol biosynthesis. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway PMID:20149798 The obligatory step in sterol biosynthesis in eukaryotes is demethylation of |
| GO:0016125 sterol metabolic process | TAS Reactome:R-HSA-211976 | MARK AS OVER ANNOTATED | Summary: Reactome TAS annotation to the broader sterol metabolic process. Correct but more general than cholesterol biosynthetic process (GO:0006695), which is the specific pathway CYP51A1 acts in. Reason: Correct parent term but less informative than the specific cholesterol biosynthetic process annotation; retained as a broader classification. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:0008398 sterol 14-demethylase activity | EXP PMID:8399332 Purification of a human cytochrome P-450 isozyme catalyzing ... | ACCEPT | Summary: Experimental (EXP) annotation from purification of the human liver P450 that catalyzes lanosterol/24,25-dihydrolanosterol 14-alpha-demethylation. This is the defining, experimentally demonstrated core catalytic function. Reason: Direct experimental support for the core molecular function; the enzyme was purified from human liver and shown to demethylate 24,25-dihydrolanosterol and its 32-hydroxy/32-oxo intermediates. Supporting Evidence: PMID:8399332 An isozyme of cytochrome P-450 catalyzing lanosterol 14 alpha-demethylation was PMID:8399332 purified from human liver using column chromatography |
| GO:0008398 sterol 14-demethylase activity | EXP PMID:8619637 The ubiquitously expressed human CYP51 encodes lanosterol 14... | ACCEPT | Summary: Experimental (EXP) annotation from cloning of human CYP51 and heterologous expression in E. coli demonstrating lanosterol 14-alpha-demethylase activity. Confirms the core catalytic function. Reason: Direct experimental support; expression of the human cDNA conferred lanosterol 14-alpha-demethylase activity. Supporting Evidence: PMID:8619637 the cDNA encodes an enzyme having lanosterol 14 alpha-demethylase activity |
| GO:0016712 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen | TAS Reactome:R-HSA-194678 | MARK AS OVER ANNOTATED | Summary: Reactome TAS annotation to a mechanistic parent term describing the P450 monooxygenase reaction coupled to a flavoprotein (NADPH-cytochrome P450 reductase) donor. Correct mechanistically but less specific than GO:0008398. Reason: Correct mechanistic description (P450 monooxygenase using NADPH-P450 reductase reducing equivalents) but a broad parent of the specific sterol 14-demethylase activity already annotated. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Cytochrome P450 monooxygenase that catalyzes the CC three-step oxidative removal of the 14alpha-methyl group (C-32) of CC sterols such as lanosterol |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-6807062 | ACCEPT | Summary: Reactome TAS annotation placing CYP51A1 in cholesterol biosynthesis (Kandutsch-Russell pathway, via 24,25-dihydrolanosterol/lathosterol). Core biological process; CYP51A1 demethylates both lanosterol and 24,25-dihydrolanosterol. Reason: Core biological process; CYP51A1 acts in both the Bloch and Kandutsch-Russell branches of cholesterol synthesis (it demethylates 24,25-dihydrolanosterol as well as lanosterol). Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt three-step oxidative removal of the 14alpha-methyl group (C-32) of CC sterols such as lanosterol (lanosta-8,24-dien-3beta-ol) and 24,25- CC dihydrolanosterol |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1655847 | ACCEPT | Summary: Reactome TAS localization to the ER membrane. Consistent with the microsomal P450 nature of CYP51A1 and with UniProt subcellular location. Reason: Well-supported core localization for this ER-membrane P450. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q64654}; Single-pass membrane protein |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-194678 | ACCEPT | Summary: Reactome TAS localization to the ER membrane (duplicate of other ER-membrane annotations). Correct core localization. Reason: Well-supported core localization; duplicate ER-membrane annotation. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q64654}; Single-pass membrane protein |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9621404 | ACCEPT | Summary: Reactome TAS localization to the ER membrane (duplicate). Correct core localization for this microsomal P450. Reason: Well-supported core localization; duplicate ER-membrane annotation. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q64654}; Single-pass membrane protein |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9947148 | ACCEPT | Summary: Reactome TAS localization to the ER membrane (duplicate), from the reaction in which CYP51A1 14-demethylates 24,25-dihydrolanosterol. Correct core localization. Reason: Well-supported core localization; duplicate ER-membrane annotation. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Endoplasmic reticulum membrane CC {ECO:0000250|UniProtKB:Q64654}; Single-pass membrane protein |
| GO:0006695 cholesterol biosynthetic process | TAS Reactome:R-HSA-191273 | ACCEPT | Summary: Reactome TAS annotation to the overall cholesterol biosynthesis pathway. Core biological process for CYP51A1. Reason: Core biological process; duplicate cholesterol biosynthesis annotation. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:0042177 negative regulation of protein catabolic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Curator sequence-similarity (ISS) transfer from mouse Cyp51 (UniProtKB:Q8K0C4), made by ARUK-UCL. An indirect, downstream physiological effect rather than the direct sterol-demethylase function of the enzyme. Reason: Indirect phenotype-level process transferred from the mouse ortholog by sequence similarity; not the core molecular function. Retained (curator-anchored) but marked non-core/over-annotated. Duplicates the IEA Ensembl-Compara annotation. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8K0C4 · Cyp51 (mouse) SUPPORTS SOURCE BUT NOT TARGET Curator ISS transfer of an indirect downstream mouse phenotype; defensible but non-core for the human enzyme. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:0050709 negative regulation of protein secretion | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Curator sequence-similarity (ISS) transfer from mouse Cyp51 (UniProtKB:Q8K0C4), made by ARUK-UCL. Indirect downstream physiological process, not the enzyme's direct function. Reason: Indirect phenotype-level process transferred from the mouse ortholog; not a core molecular function. Retained but non-core. Duplicates the IEA Ensembl-Compara annotation. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8K0C4 · Cyp51 (mouse) SUPPORTS SOURCE BUT NOT TARGET Curator ISS transfer of an indirect downstream mouse phenotype; non-core for the human enzyme. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:1900222 negative regulation of amyloid-beta clearance | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Curator sequence-similarity (ISS) transfer from mouse Cyp51 (UniProtKB:Q8K0C4), made by ARUK-UCL. A very indirect neurobiological phenotype connected to sterol/cholesterol homeostasis, not the direct molecular activity. Reason: Highly indirect disease/phenotype-level process transferred from the mouse ortholog; not part of the core sterol-biosynthetic function. Retained (curator-anchored) but strongly non-core. Duplicates the IEA Ensembl-Compara annotation. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8K0C4 · Cyp51 (mouse) SUPPORTS SOURCE BUT NOT TARGET Curator ISS transfer of a very indirect neuro/disease mouse phenotype; non-core for the human enzyme. Supporting Evidence: file:human/CYP51A1/CYP51A1-uniprot.txt Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput proteomics (HDA) detection of CYP51A1 in a membrane-proteome preparation (NK-like cell line). Correct that CYP51A1 is membrane-associated, but generic membrane is far less specific than its established ER-membrane localization. Reason: Correct but non-specific localization from a large-scale membrane-proteome screen; ER membrane (GO:0005789) is the informative term. Kept as a broader, non-core localization. Supporting Evidence: PMID:19946888 identified 1843 proteins with high confidence scores |
| GO:0006694 steroid biosynthetic process | IDA PMID:20149798 Structural basis of human CYP51 inhibition by antifungal azo... | MARK AS OVER ANNOTATED | Summary: Direct-assay (IDA) annotation to steroid biosynthetic process from the structural/functional CYP51 study. CYP51A1 acts in sterol (cholesterol) biosynthesis; steroid biosynthetic process is a correct but broader parent of cholesterol biosynthetic process. Reason: Correct but more general than the specific cholesterol biosynthetic process (GO:0006695). CYP51A1's committed role is in sterol/cholesterol synthesis; kept as a broader classification. Supporting Evidence: PMID:20149798 The obligatory step in sterol biosynthesis in eukaryotes is demethylation of |
| GO:0008398 sterol 14-demethylase activity | IDA PMID:20149798 Structural basis of human CYP51 inhibition by antifungal azo... | ACCEPT | Summary: Direct-assay (IDA) annotation of the core catalytic function from the human CYP51 crystallographic and functional study. Confirms sterol 14-demethylase activity as the defining molecular function. Reason: Core molecular function with direct structural/functional support; CYP51 demethylates sterol precursors at C14 in three sequential reactions. Supporting Evidence: PMID:20149798 which is catalyzed by CYP51 PMID:20149798 in three sequential reactions |
| GO:0020037 heme binding | IDA PMID:20149798 Structural basis of human CYP51 inhibition by antifungal azo... | ACCEPT | Summary: Direct-assay (IDA) annotation of heme binding from the crystal structures of human CYP51, which resolved the enzyme in complex with heme. Heme is the essential redox cofactor of this P450. Reason: Core cofactor binding directly demonstrated by the ligand-bound crystal structures. Supporting Evidence: PMID:20149798 Three crystal structures of human CYP51, ligand-free and complexed with antifungal drugs ketoconazole and econazole file:human/CYP51A1/CYP51A1-uniprot.txt Name=heme; Xref=ChEBI:CHEBI:30413 |
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