CYP51A1

UniProt ID: Q16850
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

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.

Existing Annotations Review

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

Core Functions

Cytochrome P450 sterol 14-alpha-demethylase; a heme/iron-dependent monooxygenase that catalyzes the three-step oxidative removal of the 14-alpha-methyl group of lanosterol and 24,25-dihydrolanosterol, the first committed post-lanosterol step of cholesterol biosynthesis, acting in the endoplasmic reticulum membrane.

Molecular Function:
sterol 14-demethylase activity
Directly Involved In:
cholesterol biosynthetic process
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • PMID:20149798
    which is catalyzed by CYP51
  • PMID:8619637
    the cDNA encodes an enzyme having lanosterol 14 alpha-demethylase activity
  • file:human/CYP51A1/CYP51A1-uniprot.txt
    Sterol 14alpha-demethylase that plays a critical role in the CC cholesterol biosynthesis pathway

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:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:19946888
Defining the membrane proteome of NK cells.
PMID:20149798
Structural basis of human CYP51 inhibition by antifungal azoles.
PMID:8399332
Purification of a human cytochrome P-450 isozyme catalyzing lanosterol 14 alpha-demethylation.
PMID:8619637
The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols.
file:human/CYP51A1/CYP51A1-uniprot.txt
UniProtKB entry Q16850 (CP51A_HUMAN), Lanosterol 14-alpha demethylase
Reactome:R-HSA-1655847
Expression of Lanosterol Demethylase (CYP51A1)
Reactome:R-HSA-191273
Cholesterol biosynthesis
Reactome:R-HSA-194678
CYP51A1 demethylates LAN
Reactome:R-HSA-211976
Endogenous sterols
Reactome:R-HSA-6807047
Cholesterol biosynthesis via desmosterol (Bloch pathway)
Reactome:R-HSA-6807062
Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)
Reactome:R-HSA-9621404
CYP51A1 gene expression
Reactome:R-HSA-9947148
CYP51A1 14-demethylates 24,25-dhLAN to 4,4-diMeCholesta-8,14-dien-3-ol

📚 Additional Documentation

Notes

(CYP51A1-notes.md)

CYP51A1 (Q16850) review notes

Identity and core function

CYP51A1 = lanosterol 14-alpha-demethylase (LDM; sterol 14alpha-demethylase; P450 51A1; EC 1.14.14.154).
Cytochrome P450 monooxygenase (heme-thiolate, axial Cys binding residue at position 455, ligand Fe;
[file:human/CYP51A1/CYP51A1-uniprot.txt "axial binding residue"]). It is the only P450 species conserved
across phyla (animals, fungi, plants) PMID:8619637.

Catalyses the first post-lanosterol step of cholesterol biosynthesis: the three-step oxidative removal of the
14alpha-methyl group (C-32) of lanosterol and 24,25-dihydrolanosterol, released as formate, producing
4,4-dimethyl-cholesta-dienols (FF-MAS type intermediates) [file:human/CYP51A1/CYP51A1-uniprot.txt "the three-step oxidative removal of the"].
In mammals CYP51 also produces meiosis-activating sterols PMID:20149798.

Evidence highlights

  • Purified human liver P450 catalysing lanosterol 14alpha-demethylation; demethylated 24,25-dihydrolanosterol
    and its oxygenated intermediates (32-OH, 32-oxo) to 4,4-dimethylcholesta-8,14-dien-3beta-ol
    PMID:8399332.
  • cDNA cloned; E. coli expression confers lanosterol 14alpha-demethylase activity; expression regulated by
    oxysterols (SREBP-type sterol feedback) PMID:8619637.
  • Crystal structures (ligand-free + ketoconazole/econazole) confirm heme cofactor and monooxygenase mechanism;
    target of azole antifungals PMID:20149798.
  • ER membrane, single-pass membrane protein (TM 30-50) [file:human/CYP51A1/CYP51A1-uniprot.txt "Endoplasmic reticulum membrane"].
  • Post-translationally regulated by MARCHF6 E3 ligase ubiquitination -> proteasomal degradation
    (PubMed:31904814; abstract not cached).

Localization

ER membrane (GO:0005789) is well supported (Reactome TAS; UniProt SubCell; GO-CAM 6796b94c00001560).
GO:0016020 "membrane" (HDA, PMID:19946888, NK-cell membrane proteome) is a generic proteomics-detection
localization; less informative than ER membrane but not wrong -> keep as non-core.

BP annotations to scrutinize

The Ensembl-Compara (IEA GO_REF:0000107) and ARUK-UCL (ISS GO_REF:0000024) annotations transferred from mouse
Cyp51 ortholog (UniProtKB:Q8K0C4):
- GO:0042177 negative regulation of protein catabolic process
- GO:0050709 negative regulation of protein secretion
- GO:1900222 negative regulation of amyloid-beta clearance
These are indirect/downstream phenotypic effects (likely from a specific mouse study linking cholesterol-synthesis
enzymes to APP/amyloid handling), not the core enzymatic function. Marked non-core / over-annotated; the ISS pair
is a curator sequence-similarity transfer so retained (not removed).

GO-CAM

Model gomodel:6796b94c00001560 "Cholesterol biosynthesis from lanosterol (Human)": CYP51A1 activity =
GO:0008398 sterol 14-demethylase activity, part_of GO:0006695 cholesterol biosynthetic process,
occurs_in GO:0005789 endoplasmic reticulum membrane. Confirms the core-function triple used here.

Core function summary

MF: GO:0008398 sterol 14-demethylase activity (heme/iron-dependent P450 monooxygenase).
BP: GO:0006695 cholesterol biosynthetic process (first post-lanosterol step).
CC: GO:0005789 endoplasmic reticulum membrane.
No common Mendelian disease (rare recessive CYP51A1 deficiency described as a cataract-hepatopathy syndrome per
Orphanet 521432, but not a common disorder).

📄 View Raw YAML

 
id: Q16850
gene_symbol: CYP51A1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: Q16850-1
- name: '2'
  id: Q16850-2
  sequence_note: VSP_037413
existing_annotations:
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: PANTHER:PTN001209376
        source_label: sterol 14-alpha demethylase family
        source_status: SUPPORTS_TRANSFER
        comment: Family-level IBA correctly places CYP51A1 as an oxidoreductase, but
          the child term GO:0008398 is the informative activity for this ortholog.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Cytochrome P450 monooxygenase that catalyzes the\nCC       three-step\
        \ oxidative removal of the 14alpha-methyl group (C-32) of\nCC       sterols\
        \ such as lanosterol"
- term:
    id: GO:0004497
    label: monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Accurate mechanistic class (monooxygenase) but less specific than GO:0008398
      sterol 14-demethylase activity; kept as a correct broader term.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Cytochrome P450 monooxygenase that catalyzes the\nCC       three-step\
        \ oxidative removal of the 14alpha-methyl group (C-32) of\nCC       sterols\
        \ such as lanosterol"
- 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 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.
    action: ACCEPT
    reason: Directly supported by the structure and cofactor assignment; the heme
      iron is essential to catalysis.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: axial binding residue
    - reference_id: PMID:20149798
      supporting_text: "Three crystal structures of \nhuman CYP51, ligand-free and\
        \ complexed with antifungal drugs ketoconazole and \neconazole"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Well-supported localization; ER membrane is the established site of CYP51A1
      catalysis in the sterol biosynthetic pathway.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane\nCC       {ECO:0000250|UniProtKB:Q64654};\
        \ Single-pass membrane protein"
- term:
    id: GO:0008398
    label: sterol 14-demethylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core molecular function; correct and specific.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: EC=1.14.14.154
- 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) 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).
    action: MARK_AS_OVER_ANNOTATED
    reason: Correct mechanistic parent but redundant with the more specific catalytic
      activity term already annotated.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Cytochrome P450 monooxygenase that catalyzes the\nCC       three-step\
        \ oxidative removal of the 14alpha-methyl group (C-32) of\nCC       sterols\
        \ such as lanosterol"
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Directly supported; heme is the redox-active prosthetic group required
      for catalysis. Duplicates the IDA heme-binding annotation from PMID:20149798.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: Name=heme; Xref=ChEBI:CHEBI:30413
- term:
    id: GO:0042177
    label: negative regulation of protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:Q8K0C4
        source_label: Cyp51 (mouse)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Indirect downstream physiology of the mouse ortholog; defensible but
          not a core molecular activity of human CYP51A1.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:0050709
    label: negative regulation of protein secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Automated Ensembl-Compara ortholog transfer (IEA) from mouse Cyp51 (UniProtKB:Q8K0C4).
      An indirect, downstream physiological process, not the direct enzymatic function
      of CYP51A1.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:Q8K0C4
        source_label: Cyp51 (mouse)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Indirect downstream physiology of the mouse ortholog; not a core
          activity of human CYP51A1.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:1900222
    label: negative regulation of amyloid-beta clearance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:Q8K0C4
        source_label: Cyp51 (mouse)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Very indirect neuro/disease phenotype of the mouse ortholog; not a
          core molecular activity of human CYP51A1.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807047
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Core biological process; the 14-alpha-demethylation step is an obligatory
      part of cholesterol biosynthesis.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
    - reference_id: PMID:20149798
      supporting_text: The obligatory step in sterol biosynthesis in eukaryotes is
        demethylation of
- 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 to the broader sterol metabolic process. Correct
      but more general than cholesterol biosynthetic process (GO:0006695), which is
      the specific pathway CYP51A1 acts in.
    action: MARK_AS_OVER_ANNOTATED
    reason: Correct parent term but less informative than the specific cholesterol
      biosynthetic process annotation; retained as a broader classification.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:0008398
    label: sterol 14-demethylase activity
  evidence_type: EXP
  original_reference_id: PMID:8399332
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:8399332
      supporting_text: An isozyme of cytochrome P-450 catalyzing lanosterol 14 alpha-demethylation
        was
    - reference_id: PMID:8399332
      supporting_text: purified from human liver using column chromatography
- term:
    id: GO:0008398
    label: sterol 14-demethylase activity
  evidence_type: EXP
  original_reference_id: PMID:8619637
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Direct experimental support; expression of the human cDNA conferred lanosterol
      14-alpha-demethylase activity.
    supported_by:
    - reference_id: PMID:8619637
      supporting_text: "the cDNA encodes an enzyme having lanosterol 14 alpha-demethylase\
        \ \nactivity"
- term:
    id: GO:0016712
    label: 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
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194678
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Cytochrome P450 monooxygenase that catalyzes the\nCC       three-step\
        \ oxidative removal of the 14alpha-methyl group (C-32) of\nCC       sterols\
        \ such as lanosterol"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807062
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "three-step oxidative removal of the 14alpha-methyl group (C-32)\
        \ of\nCC       sterols such as lanosterol (lanosta-8,24-dien-3beta-ol) and\
        \ 24,25-\nCC       dihydrolanosterol"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655847
  qualifier: located_in
  review:
    summary: Reactome TAS localization to the ER membrane. Consistent with the microsomal
      P450 nature of CYP51A1 and with UniProt subcellular location.
    action: ACCEPT
    reason: Well-supported core localization for this ER-membrane P450.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane\nCC       {ECO:0000250|UniProtKB:Q64654};\
        \ Single-pass membrane protein"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-194678
  qualifier: located_in
  review:
    summary: Reactome TAS localization to the ER membrane (duplicate of other ER-membrane
      annotations). Correct core localization.
    action: ACCEPT
    reason: Well-supported core localization; duplicate ER-membrane annotation.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane\nCC       {ECO:0000250|UniProtKB:Q64654};\
        \ Single-pass membrane protein"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9621404
  qualifier: located_in
  review:
    summary: Reactome TAS localization to the ER membrane (duplicate). Correct core
      localization for this microsomal P450.
    action: ACCEPT
    reason: Well-supported core localization; duplicate ER-membrane annotation.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane\nCC       {ECO:0000250|UniProtKB:Q64654};\
        \ Single-pass membrane protein"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9947148
  qualifier: located_in
  review:
    summary: Reactome TAS localization to the ER membrane (duplicate), from the reaction
      in which CYP51A1 14-demethylates 24,25-dihydrolanosterol. Correct core localization.
    action: ACCEPT
    reason: Well-supported core localization; duplicate ER-membrane annotation.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Endoplasmic reticulum membrane\nCC       {ECO:0000250|UniProtKB:Q64654};\
        \ Single-pass membrane protein"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191273
  qualifier: involved_in
  review:
    summary: Reactome TAS annotation to the overall cholesterol biosynthesis pathway.
      Core biological process for CYP51A1.
    action: ACCEPT
    reason: Core biological process; duplicate cholesterol biosynthesis annotation.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:0042177
    label: negative regulation of protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:Q8K0C4
        source_label: Cyp51 (mouse)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Curator ISS transfer of an indirect downstream mouse phenotype; defensible
          but non-core for the human enzyme.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:0050709
    label: negative regulation of protein secretion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:Q8K0C4
        source_label: Cyp51 (mouse)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Curator ISS transfer of an indirect downstream mouse phenotype; non-core
          for the human enzyme.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:1900222
    label: negative regulation of amyloid-beta clearance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:Q8K0C4
        source_label: Cyp51 (mouse)
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: Curator ISS transfer of a very indirect neuro/disease mouse phenotype;
          non-core for the human enzyme.
    supported_by:
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
        CC       cholesterol biosynthesis pathway"
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: identified 1843 proteins with high confidence scores
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:20149798
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:20149798
      supporting_text: The obligatory step in sterol biosynthesis in eukaryotes is
        demethylation of
- term:
    id: GO:0008398
    label: sterol 14-demethylase activity
  evidence_type: IDA
  original_reference_id: PMID:20149798
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core molecular function with direct structural/functional support; CYP51
      demethylates sterol precursors at C14 in three sequential reactions.
    supported_by:
    - reference_id: PMID:20149798
      supporting_text: which is catalyzed by CYP51
    - reference_id: PMID:20149798
      supporting_text: in three sequential reactions
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IDA
  original_reference_id: PMID:20149798
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core cofactor binding directly demonstrated by the ligand-bound crystal
      structures.
    supported_by:
    - reference_id: PMID:20149798
      supporting_text: "Three crystal structures of \nhuman CYP51, ligand-free and\
        \ complexed with antifungal drugs ketoconazole and \neconazole"
    - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
      supporting_text: Name=heme; Xref=ChEBI:CHEBI:30413
core_functions:
- description: Cytochrome P450 sterol 14-alpha-demethylase; a heme/iron-dependent
    monooxygenase that catalyzes the three-step oxidative removal of the 14-alpha-methyl
    group of lanosterol and 24,25-dihydrolanosterol, the first committed post-lanosterol
    step of cholesterol biosynthesis, acting in the endoplasmic reticulum membrane.
  molecular_function:
    id: GO:0008398
    label: sterol 14-demethylase activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:20149798
    supporting_text: which is catalyzed by CYP51
  - reference_id: PMID:8619637
    supporting_text: "the cDNA encodes an enzyme having lanosterol 14 alpha-demethylase\
      \ \nactivity"
  - reference_id: file:human/CYP51A1/CYP51A1-uniprot.txt
    supporting_text: "Sterol 14alpha-demethylase that plays a critical role in the\n\
      CC       cholesterol biosynthesis pathway"
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput NK-cell membrane proteome; supports only generic
      membrane detection of CYP51A1, not ER-specific localization or function.
- id: PMID:20149798
  title: Structural basis of human CYP51 inhibition by antifungal azoles.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystal structures of human CYP51 confirm heme cofactor, monooxygenase
      mechanism, sterol 14-demethylase activity, and azole binding.
- id: PMID:8399332
  title: Purification of a human cytochrome P-450 isozyme catalyzing lanosterol 14
    alpha-demethylation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Purified the human liver P450 with lanosterol/24,25-dihydrolanosterol
      14-alpha-demethylase activity; primary experimental support for the core function.
- id: PMID:8619637
  title: The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase,
    a cytochrome P450 whose expression is regulated by oxysterols.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cloned human CYP51; E. coli expression confers lanosterol 14-alpha-demethylase
      activity; establishes oxysterol-regulated ubiquitous expression.
- id: file:human/CYP51A1/CYP51A1-uniprot.txt
  title: UniProtKB entry Q16850 (CP51A_HUMAN), Lanosterol 14-alpha demethylase
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: UniProt curated record; source for function, catalytic activity,
      heme cofactor, ER-membrane localization, and pathway placement.
- id: Reactome:R-HSA-1655847
  title: Expression of Lanosterol Demethylase (CYP51A1)
  findings: []
- id: Reactome:R-HSA-191273
  title: Cholesterol biosynthesis
  findings: []
- id: Reactome:R-HSA-194678
  title: CYP51A1 demethylates LAN
  findings: []
- id: Reactome:R-HSA-211976
  title: Endogenous sterols
  findings: []
- id: Reactome:R-HSA-6807047
  title: Cholesterol biosynthesis via desmosterol (Bloch pathway)
  findings: []
- id: Reactome:R-HSA-6807062
  title: Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)
  findings: []
- id: Reactome:R-HSA-9621404
  title: CYP51A1 gene expression
  findings: []
- id: Reactome:R-HSA-9947148
  title: CYP51A1 14-demethylates 24,25-dhLAN to 4,4-diMeCholesta-8,14-dien-3-ol
  findings: []