id: P22680
gene_symbol: CYP7A1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Cholesterol 7-alpha-hydroxylase (cytochrome P450 7A1), the rate-limiting,
  committed first enzyme of the classic (neutral) bile-acid biosynthesis pathway.
  It is a heme-thiolate cytochrome P450 monooxygenase of the endoplasmic reticulum
  membrane that hydroxylates cholesterol at the 7-alpha position to yield
  7-alpha-hydroxycholesterol, consuming molecular oxygen and reducing equivalents
  supplied by NADPH via cytochrome P450 reductase. This 7-alpha-hydroxylation is the
  rate-controlling step that commits hepatic cholesterol to catabolism and bile-acid
  synthesis; the enzyme also 7-alpha-hydroxylates several oxysterols (for example
  24-hydroxycholesterol and 4-beta-hydroxycholesterol) as a minor activity. CYP7A1 is
  expressed almost exclusively in liver, and its transcription is tightly, dynamically
  regulated: it is repressed by bile acids through FXR-dependent feedback and induced
  by conditions such as glucose and cholestyramine, allowing bile-acid output to be
  matched to physiological demand. Loss-of-function causes CYP7A1 deficiency, an
  autosomal disorder characterized by hepatic cholesterol accumulation,
  hypercholesterolemia and premature gallstones.
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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11013305
  title: 24-hydroxycholesterol is a substrate for hepatic cholesterol 7alpha-hydroxylase
    (CYP7A).
  findings:
  - statement: >-
      Recombinant human CYP7A shows 7-alpha-hydroxylase activity toward both
      cholesterol and the two isomers of 24-hydroxycholesterol, with a preference for
      the (24S)-isomer, establishing CYP7A1 as a cholesterol/oxysterol
      7-alpha-hydroxylase and the rate-limiting enzyme of bile acid biosynthesis.
    supporting_text: >-
      Human CYP7A, recombinantly expressed in Escherichia coli and in simian COS cells,
      showed 7alpha-hydroxylase activity toward both cholesterol and the two isomers of
      24-hydroxycholesterol
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified abstract (J Lipid Res 2000). Directly supports both the core
      cholesterol 7-alpha-monooxygenase activity and the minor 24S-hydroxycholesterol
      7-alpha-hydroxylase activity (EC 1.14.14.26).
- id: PMID:12077124
  title: Metabolism of 4 beta -hydroxycholesterol in humans.
  findings:
  - statement: >-
      Recombinant human CYP7A1 7-alpha-hydroxylates 4-beta-hydroxycholesterol, albeit
      more slowly than cholesterol, confirming direct sterol 7-alpha-hydroxylase activity
      of the human enzyme.
    supporting_text: >-
      beta-hydroxycholesterol was 7 alpha-hydroxylated at a slower rate than cholesterol
      by recombinant human CYP7A1
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified abstract (J Biol Chem 2002). Basis for the IDA cholesterol
      7-alpha-monooxygenase activity annotation on recombinant human CYP7A1.
- id: PMID:19965590
  title: Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human
    hepatocytes.
  findings:
  - statement: >-
      High glucose induces CYP7A1 mRNA and stimulates bile-acid synthesis in human
      hepatocytes; CYP7A1 is described as the key regulatory gene in bile acid synthesis,
      induced via an HNF4alpha-dependent, AMPK-modulated, epigenetic mechanism.
    supporting_text: >-
      High glucose stimulated bile acid synthesis and induced mRNA expression of
      cholesterol ... 7alpha-hydroxylase (CYP7A1), the key regulatory gene in bile acid
      synthesis
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified abstract (J Lipid Res 2010). This is a study of transcriptional
      regulation of the CYP7A1 gene; supports response-to-glucose and
      bile-acid-synthesis regulatory annotations, but the enzyme's own molecular action
      is the 7-alpha-hydroxylase activity.
- id: PMID:2384150
  title: Molecular cloning and sequence analysis of cDNA encoding human cholesterol
    7 alpha-hydroxylase.
  findings:
  - statement: >-
      The human CYP7A1 cDNA encodes a 504-residue cholesterol 7-alpha-hydroxylase with
      conserved heme- and steroid-binding domains characteristic of steroidogenic
      cytochrome P450s.
    supporting_text: >-
      A complete cDNA clone encoding human cholesterol 7 ... alpha-hydroxylase has been
      isolated ... Unique amino acid residues were observed in putative binding domains
      for heme and steroid which are highly conserved in most steroidogenic P-450s
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified abstract (FEBS Lett 1990), the human cloning/sequence paper.
      UniProt attaches CATALYTIC ACTIVITY / FUNCTION / PATHWAY / SUBCELLULAR LOCATION
      (EC 1.14.14.23) to this reference; the abstract is cloning-focused, so the
      enzymatic assay was in the full text.
- id: Reactome:R-HSA-192051
  title: CYP7A1 7-hydroxylates CHOL
  findings:
  - statement: >-
      CYP7A1 catalyses cholesterol + NADPH + H+ + O2 to 7alpha-cholesterol + NADP+ + H2O
      in the endoplasmic reticulum membrane; the enzyme is expressed only in liver and
      is transcriptionally regulated to set the overall rate of bile acid/bile salt
      production.
    supporting_text: >-
      reaction catalysed by CYP7A1 (cholesterol 7alpha-hydroylase) in the endoplasmic
      reticulum membrane
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction for the committed cholesterol 7-alpha-hydroxylation step,
      localized to the ER membrane. Title left as fetched.
- id: Reactome:R-HSA-193368
  title: Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
  findings:
  - statement: >-
      The classic (neutral) hepatic bile-acid biosynthesis pathway is initiated by
      conversion of cholesterol to 7alpha-hydroxycholesterol (the CYP7A1 step).
    supporting_text: >-
      synthesis of bile acids and bile salts is initiated with the conversion of
      cholesterol to 7alpha-hydroxycholesterol
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome pathway placing CYP7A1 at the entry point of classic bile acid synthesis.
      Title left as fetched.
- id: Reactome:R-HSA-1989746
  title: Expression of CYP7A1
  findings:
  - statement: >-
      Reactome event representing transcription/translation of the CYP7A1 gene; relevant
      to the transcriptional-regulation biology but not to the enzyme's molecular
      localization.
    supporting_text: >-
      The CYP7A1 gene is transcribed to yield mRNA and the mRNA is translated to yield
      protein
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      This is a gene-expression event; GOA nonetheless cites it (TAS) for an ER-membrane
      localization, which is better supported by R-HSA-192051 and by UniProt. Title left
      as fetched.
- id: Reactome:R-HSA-211976
  title: Endogenous sterols
  findings:
  - statement: >-
      A number of cytochrome P450s (including CYP7A1) participate in cholesterol
      elimination and homeostasis, degrading cholesterol to bile salts.
    supporting_text: >-
      A number of CYPs take part in cholesterol biosynthesis and elimination, thus
      playing an important role in maintaining cholesterol homeostasis
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome grouping of sterol-metabolizing CYPs; supports the sterol metabolic
      process / cholesterol homeostasis context. Title left as fetched.
- id: file:human/CYP7A1/CYP7A1-uniprot.txt
  title: UniProtKB P22680 (CP7A1_HUMAN) curated entry
  findings:
  - statement: >-
      CYP7A1 is a cytochrome P450 monooxygenase that catalyses 7-alpha hydroxylation of
      cholesterol, the rate-limiting step in cholesterol catabolism and bile acid
      biosynthesis, and is a critical regulatory enzyme of bile acid biosynthesis and
      cholesterol homeostasis.
    supporting_text: >-
      Functions as a critical regulatory enzyme of bile acid biosynthesis and cholesterol
      homeostasis. Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position
      of cholesterol, a rate-limiting step in cholesterol catabolism and bile acid
      biosynthesis
  - statement: >-
      The enzyme is localized to the endoplasmic reticulum (microsome) membrane as a
      single-pass membrane protein and uses heme as cofactor.
    supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Local cached UniProt record; verbatim FUNCTION and SUBCELLULAR LOCATION lines
      quoted.
existing_annotations:
- term:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function. Phylogenetic (IBA) annotation to the defining catalytic
      activity of CYP7A1, the cholesterol 7-alpha-hydroxylase, agreeing with experimental
      evidence and UniProt.
    action: ACCEPT
    reason: >-
      This is the well-established, defining molecular function of CYP7A1
      (EC 1.14.14.23), supported by direct experimental assays of the recombinant human
      enzyme and by UniProt.
    supported_by:
    - reference_id: PMID:11013305
      supporting_text: >-
        Human CYP7A, recombinantly expressed in Escherichia coli and in simian COS cells,
        showed 7alpha-hydroxylase activity toward both cholesterol
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of
        cholesterol
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. CYP7A1 catalyses the committed, rate-limiting first step
      of the classic (neutral) bile-acid biosynthesis pathway.
    action: ACCEPT
    reason: >-
      The 7-alpha-hydroxylation of cholesterol initiates classic bile-acid synthesis;
      this is the central physiological role of the enzyme, consistent across IBA, ISS,
      IDA and IEA evidence and with Reactome.
    supported_by:
    - reference_id: Reactome:R-HSA-193368
      supporting_text: >-
        synthesis of bile acids and bile salts is initiated with the conversion of
        cholesterol to 7alpha-hydroxycholesterol
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        a rate-limiting step in cholesterol catabolism and bile acid biosynthesis
- term:
    id: GO:0042632
    label: cholesterol homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      CYP7A1, as the rate-limiting enzyme of bile-acid synthesis (the major route of
      cholesterol elimination), is a key contributor to whole-body cholesterol
      homeostasis. This is a physiological/pathway-level outcome rather than the enzyme's
      molecular action.
    action: KEEP_AS_NON_CORE
    reason: >-
      Well-supported physiological role (UniProt: critical regulatory enzyme of bile acid
      biosynthesis and cholesterol homeostasis; loss of function causes
      hypercholesterolemia), but it is downstream of the catalytic activity rather than a
      core molecular function, so it is retained as non-core.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis
    - reference_id: Reactome:R-HSA-211976
      supporting_text: playing an important role in maintaining cholesterol homeostasis
- term:
    id: GO:0004497
    label: monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Correct but general parent-level InterPro-based annotation. CYP7A1 is a cytochrome
      P450 monooxygenase; the more specific child term GO:0008123 is the informative core
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Accurate at the family level (cytochrome P450 monooxygenase) but subsumed by the
      specific cholesterol 7-alpha-monooxygenase activity; kept as a correct but
      redundant/general annotation.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in the metabolism of endogenous
        cholesterol
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Core-supporting cofactor function. As a heme-thiolate cytochrome P450, CYP7A1 binds
      the heme iron essential for its monooxygenase catalysis; the crystal structure
      identifies Cys444 as the axial heme-Fe ligand.
    action: ACCEPT
    reason: >-
      CYP7A1 is a heme protein whose catalysis depends on the heme iron (axial Cys444
      ligand from the crystal structure); iron binding is a valid, catalytically essential
      cofactor annotation.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: /ligand_part="Fe"
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Core cellular component. CYP7A1 is an ER (microsomal) membrane cytochrome P450,
      anchored by an N-terminal transmembrane helix (residues 4-24).
    action: ACCEPT
    reason: >-
      Well-established microsomal/ER-membrane localization, supported by UniProt
      subcellular location, the N-terminal transmembrane feature, and Reactome.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
    - reference_id: Reactome:R-HSA-192051
      supporting_text: >-
        catalysed by CYP7A1 (cholesterol 7alpha-hydroylase) in the endoplasmic reticulum
        membrane
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Core biological process (electronic duplicate of the IBA/ISS/IDA annotations).
      CYP7A1 initiates the classic bile-acid biosynthesis pathway.
    action: ACCEPT
    reason: Correct and consistent with all other evidence lines for this process.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: bile acid biosynthesis
- term:
    id: GO:0006707
    label: cholesterol catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. Conversion of cholesterol to bile acids is the major route
      of cholesterol catabolism/elimination, and CYP7A1 catalyses its rate-limiting step.
    action: ACCEPT
    reason: >-
      UniProt explicitly describes the 7-alpha-hydroxylation as a rate-limiting step in
      cholesterol catabolism; correct and central.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        a rate-limiting step in cholesterol catabolism and bile acid biosynthesis
- term:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Core molecular function (electronic duplicate). Matches the RHEA:21812 /
      EC 1.14.14.23 reaction.
    action: ACCEPT
    reason: Correct; identical to the experimentally supported core MF.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of
        cholesterol
- term:
    id: GO:0008206
    label: bile acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Correct but general (ARBA) parent of bile acid biosynthetic process. The more
      specific GO:0006699 is the informative annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      True but redundant with the more specific bile acid biosynthetic process
      annotation; retained as a correct general term.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: bile acid biosynthesis
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Correct but general (ARBA) term. CYP7A1 metabolizes cholesterol (a sterol) and
      oxysterols; subsumed by the more specific cholesterol catabolic / bile acid
      biosynthetic process terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Accurate at a high level but less informative than the specific process terms
      already present.
    supported_by:
    - reference_id: Reactome:R-HSA-211976
      supporting_text: >-
        A number of CYPs take part in cholesterol biosynthesis and elimination
- 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: >-
      Correct but general parent-level (InterPro) term describing the P450 monooxygenase
      chemistry. Subsumed by the specific GO:0008123.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Accurate class-level description of the catalytic mechanism (inserting one O atom,
      reducing the other to water using NADPH-CPR electrons) but less informative than the
      specific activity term.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the
        second into a water molecule
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Core-supporting cofactor function. CYP7A1 is a heme-thiolate P450; the crystal
      structure (Ref.12) contains heme, with Cys444 as the axial heme-Fe ligand.
    action: ACCEPT
    reason: >-
      Heme is the essential cofactor of this cytochrome P450 (COFACTOR heme; structural
      evidence); a valid, catalytically required binding annotation.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: 'Name=heme; Xref=ChEBI:CHEBI:30413'
- term:
    id: GO:0033782
    label: 24S-hydroxycholesterol 7-alpha-hydroxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Genuine minor/secondary catalytic activity (EC 1.14.14.26, RHEA:46124). Recombinant
      human CYP7A1 7-alpha-hydroxylates 24S-hydroxycholesterol, a brain-derived oxysterol
      eliminated in the liver.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally demonstrated (PMID:11013305) but a secondary activity relative to the
      core cholesterol 7-alpha-hydroxylation; retained as non-core.
    supported_by:
    - reference_id: PMID:11013305
      supporting_text: >-
        showed 7alpha-hydroxylase activity toward both cholesterol and the two isomers of
        24-hydroxycholesterol, with a preference for the
- term:
    id: GO:0042632
    label: cholesterol homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic duplicate of the cholesterol homeostasis annotation; a
      physiological/pathway-level outcome of CYP7A1's rate-limiting role in cholesterol
      elimination.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct physiological role but downstream of the molecular activity; kept as
      non-core, consistent with the IBA/ISS duplicates.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis
- term:
    id: GO:0071333
    label: cellular response to glucose stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      CYP7A1 transcription is induced by glucose in human hepatocytes. This is a
      transcriptional-response property of the gene, not a molecular function of the
      protein.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported (PMID:19965590) but reflects regulation of the gene rather
      than the enzyme's molecular action; retained as non-core.
    supported_by:
    - reference_id: PMID:19965590
      supporting_text: >-
        High glucose stimulated bile acid synthesis and induced mRNA expression of
        cholesterol
- term:
    id: GO:0032966
    label: negative regulation of collagen biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transferred (Ensembl Compara, from rat CYP7A1 P18125) indirect
      phenotype-derived term. There is no evidence that CYP7A1 directly regulates collagen
      biosynthesis; any effect would be an indirect, systemic consequence.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Automatically transferred from a rat ortholog and not reflective of a direct CYP7A1
      molecular/biological function; likely an indirect downstream physiological correlate
      rather than a bona fide process the enzyme is involved in.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in the metabolism of endogenous
        cholesterol
- term:
    id: GO:0045471
    label: response to ethanol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transferred (Ensembl Compara, from rat P18125) physiological response term.
      Plausible for a hepatic drug/lipid-metabolizing enzyme but not a core function and
      not directly demonstrated for human CYP7A1 here.
    action: KEEP_AS_NON_CORE
    reason: >-
      Plausible physiological response inherited from the rat ortholog; retained as
      non-core pending direct human evidence rather than removed.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in the metabolism of endogenous
        cholesterol
- term:
    id: GO:0045542
    label: positive regulation of cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transferred (Ensembl Compara, from rat P18125). CYP7A1 is a
      cholesterol-catabolic enzyme; any positive effect on cholesterol biosynthesis would
      be an indirect homeostatic feedback rather than a direct function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Counterintuitive for a catabolic enzyme and inherited by automated ortholog
      transfer; represents an indirect homeostatic correlate, not a direct role of CYP7A1
      in promoting cholesterol synthesis.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: metabolism of endogenous cholesterol
- term:
    id: GO:0045717
    label: negative regulation of fatty acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transferred (Ensembl Compara, from rat P18125) indirect metabolic term.
      Not a direct molecular function of CYP7A1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Automatically transferred from a rat ortholog; likely an indirect systemic-metabolism
      correlate (bile-acid/lipid signaling) rather than a direct CYP7A1 activity.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        A cytochrome P450 monooxygenase involved in the metabolism of endogenous
        cholesterol
- term:
    id: GO:0070857
    label: regulation of bile acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      As the rate-limiting enzyme whose expression sets the flux through bile-acid
      synthesis, CYP7A1 is central to regulation of the pathway. This is a
      pathway-regulatory role rather than the enzyme's molecular action.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by the enzyme's rate-limiting position and its tight transcriptional
      control (glucose, bile-acid/FXR feedback), but downstream of the catalytic activity;
      kept as non-core.
    supported_by:
    - reference_id: PMID:19965590
      supporting_text: the key regulatory gene in bile acid synthesis
- term:
    id: GO:0071397
    label: cellular response to cholesterol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      CYP7A1 responds to and metabolizes cellular cholesterol/oxysterols; its
      transcription is part of cholesterol-driven homeostatic control. Non-core
      physiological response.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the enzyme's role in cholesterol homeostasis and its regulation, but
      a downstream response rather than the core molecular function.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        metabolism of endogenous cholesterol and its oxygenated derivatives (oxysterols)
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193368
  qualifier: involved_in
  review:
    summary: >-
      Core biological process, curated by Reactome as the classic bile-acid synthesis
      pathway initiated by CYP7A1.
    action: ACCEPT
    reason: Authoritative Reactome curation consistent with all other evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-193368
      supporting_text: >-
        synthesis of bile acids and bile salts is initiated with the conversion of
        cholesterol to 7alpha-hydroxycholesterol
- term:
    id: GO:0016125
    label: sterol metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-211976
  qualifier: involved_in
  review:
    summary: >-
      Correct but general Reactome-curated term (CYP7A1 within the Endogenous sterols
      grouping). Subsumed by the specific cholesterol catabolic / bile acid biosynthetic
      terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Accurate high-level term but less informative than the specific process annotations
      already present.
    supported_by:
    - reference_id: Reactome:R-HSA-211976
      supporting_text: >-
        A number of CYPs take part in cholesterol biosynthesis and elimination
- term:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192051
  qualifier: enables
  review:
    summary: >-
      Core molecular function, curated by Reactome as the CYP7A1 7-hydroxylation of
      cholesterol reaction.
    action: ACCEPT
    reason: >-
      Authoritative Reactome curation of the defining reaction, consistent with
      experimental and UniProt evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-192051
      supporting_text: >-
        reaction catalysed by CYP7A1 (cholesterol 7alpha-hydroylase) in the endoplasmic
        reticulum membrane
- term:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  evidence_type: EXP
  original_reference_id: PMID:11013305
  qualifier: enables
  review:
    summary: >-
      Core molecular function with direct experimental support. Recombinant human CYP7A
      shows 7-alpha-hydroxylase activity toward cholesterol.
    action: ACCEPT
    reason: Direct experimental (EXP) evidence for the defining catalytic activity.
    supported_by:
    - reference_id: PMID:11013305
      supporting_text: >-
        Human CYP7A, recombinantly expressed in Escherichia coli and in simian COS cells,
        showed 7alpha-hydroxylase activity toward both cholesterol
- term:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  evidence_type: EXP
  original_reference_id: PMID:2384150
  qualifier: enables
  review:
    summary: >-
      Core molecular function. The human cholesterol 7-alpha-hydroxylase cDNA was cloned
      and characterized; UniProt attaches the EC 1.14.14.23 catalytic activity to this
      reference.
    action: ACCEPT
    reason: >-
      Foundational human cloning/characterization paper for cholesterol
      7-alpha-hydroxylase; UniProt cites it for CATALYTIC ACTIVITY and FUNCTION. The
      cached abstract is cloning-focused, so the assay is in the full text; defer to the
      curator.
    supported_by:
    - reference_id: PMID:2384150
      supporting_text: >-
        A complete cDNA clone encoding human cholesterol 7 ... alpha-hydroxylase has been
        isolated
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: Cholesterol 7-alpha-monooxygenase
- term:
    id: GO:0033782
    label: 24S-hydroxycholesterol 7-alpha-hydroxylase activity
  evidence_type: EXP
  original_reference_id: PMID:11013305
  qualifier: enables
  review:
    summary: >-
      Genuine minor catalytic activity with direct experimental support (EC 1.14.14.26).
      Recombinant human CYP7A1 7-alpha-hydroxylates both 24-hydroxycholesterol isomers,
      preferring the (24S) form.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally demonstrated but a secondary activity relative to the core
      cholesterol 7-alpha-hydroxylation; retained as non-core.
    supported_by:
    - reference_id: PMID:11013305
      supporting_text: >-
        showed 7alpha-hydroxylase activity toward both cholesterol and the two isomers of
        24-hydroxycholesterol, with a preference for the
- term:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  evidence_type: IDA
  original_reference_id: PMID:12077124
  qualifier: enables
  review:
    summary: >-
      Core molecular function with direct assay evidence. Recombinant human CYP7A1
      7-alpha-hydroxylates a sterol substrate (4-beta-hydroxycholesterol, and cholesterol
      at a faster rate).
    action: ACCEPT
    reason: >-
      Direct (IDA) evidence that recombinant human CYP7A1 possesses sterol
      7-alpha-hydroxylase activity.
    supported_by:
    - reference_id: PMID:12077124
      supporting_text: >-
        beta-hydroxycholesterol was 7 alpha-hydroxylated at a slower rate than cholesterol
        by recombinant human CYP7A1
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192051
  qualifier: located_in
  review:
    summary: >-
      Core cellular component, Reactome-curated ER-membrane localization of the CYP7A1
      reaction.
    action: ACCEPT
    reason: >-
      Consistent with UniProt subcellular location and the N-terminal transmembrane
      anchor.
    supported_by:
    - reference_id: Reactome:R-HSA-192051
      supporting_text: >-
        catalysed by CYP7A1 (cholesterol 7alpha-hydroylase) in the endoplasmic reticulum
        membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1989746
  qualifier: located_in
  review:
    summary: >-
      ER-membrane localization annotation attributed to the Expression of CYP7A1 Reactome
      event, which is actually a gene transcription/translation event. The localization
      itself is correct (well supported by R-HSA-192051 and UniProt).
    action: ACCEPT
    reason: >-
      The ER-membrane location is correct and well supported by UniProt and by the
      companion Reactome reaction R-HSA-192051; accepted for consistency with the other
      ER-membrane annotations, though this particular source (an expression event) is a
      weaker choice of evidence for a subcellular-localization annotation.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Core biological process (sequence-similarity transfer from rat CYP7A1 P18125),
      consistent with the experimental human evidence.
    action: ACCEPT
    reason: Correct; agrees with all other evidence lines for bile-acid biosynthesis.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: bile acid biosynthesis
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19965590
  qualifier: involved_in
  review:
    summary: >-
      CYP7A1 is central to hepatic bile-acid synthesis; high glucose induced CYP7A1 and
      stimulated bile-acid synthesis in human hepatocytes.
    action: ACCEPT
    reason: >-
      Direct experimental support for CYP7A1's involvement in bile-acid synthesis in human
      hepatocytes.
    supported_by:
    - reference_id: PMID:19965590
      supporting_text: >-
        High glucose stimulated bile acid synthesis and induced mRNA expression of
        cholesterol
- term:
    id: GO:0006707
    label: cholesterol catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Core biological process (sequence-similarity transfer from rat P18125). Bile-acid
      synthesis is the major route of cholesterol catabolism.
    action: ACCEPT
    reason: >-
      Correct; consistent with UniProt describing the 7-alpha-hydroxylation as the
      rate-limiting step in cholesterol catabolism.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: a rate-limiting step in cholesterol catabolism
- term:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      Core molecular function (sequence-similarity transfer from rat P18125), matching the
      experimentally established human activity.
    action: ACCEPT
    reason: Correct; identical to the experimentally supported core MF.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of
        cholesterol
- term:
    id: GO:0042632
    label: cholesterol homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Physiological role in cholesterol homeostasis (sequence-similarity transfer from rat
      P18125); a downstream outcome of the enzyme's rate-limiting activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct physiological role but downstream of the molecular activity; kept as
      non-core, consistent with the IBA/IEA duplicates.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        critical regulatory enzyme of bile acid biosynthesis and cholesterol homeostasis
- term:
    id: GO:0043231
    label: intracellular membrane-bounded organelle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Very general cellular-component term (sequence-similarity transfer). The specific and
      well-supported localization is the endoplasmic reticulum membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: Correct but uninformatively general; subsumed by the ER-membrane annotation.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0070857
    label: regulation of bile acid biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Pathway-regulatory role (sequence-similarity transfer from rat P18125), reflecting
      CYP7A1's rate-limiting, tightly controlled position in bile-acid synthesis.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supported by the enzyme's rate-limiting position and transcriptional control, but
      downstream of the catalytic activity; non-core.
    supported_by:
    - reference_id: PMID:19965590
      supporting_text: the key regulatory gene in bile acid synthesis
- term:
    id: GO:0070857
    label: regulation of bile acid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19965590
  qualifier: involved_in
  review:
    summary: >-
      CYP7A1 is the key regulatory gene of bile-acid synthesis; its glucose-inducible
      transcription controls pathway flux. Pathway-regulatory role rather than a molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally anchored (PMID:19965590) but reflects rate-limiting/regulatory control
      of the pathway rather than the enzyme's molecular action; non-core.
    supported_by:
    - reference_id: PMID:19965590
      supporting_text: the key regulatory gene in bile acid synthesis
- term:
    id: GO:0071333
    label: cellular response to glucose stimulus
  evidence_type: IDA
  original_reference_id: PMID:19965590
  qualifier: involved_in
  review:
    summary: >-
      CYP7A1 transcription is induced by high glucose in human hepatocytes via an
      HNF4alpha-dependent, AMPK-modulated mechanism. Transcriptional response of the gene,
      not a molecular function of the protein.
    action: KEEP_AS_NON_CORE
    reason: >-
      Directly demonstrated gene-level response to glucose, but a regulatory response
      rather than a core function; non-core.
    supported_by:
    - reference_id: PMID:19965590
      supporting_text: >-
        High glucose stimulated bile acid synthesis and induced mRNA expression of
        cholesterol
- term:
    id: GO:0071397
    label: cellular response to cholesterol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      CYP7A1 responds to and metabolizes cellular cholesterol/oxysterols (sequence-similarity
      transfer from rat P18125); a downstream homeostatic response.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the enzyme's role in cholesterol homeostasis and its feedback
      regulation, but a downstream response rather than the core molecular function.
    supported_by:
    - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
      supporting_text: >-
        metabolism of endogenous cholesterol and its oxygenated derivatives (oxysterols)
core_functions:
- description: >-
    Cholesterol 7-alpha-hydroxylase (cytochrome P450 7A1) catalysing the committed,
    rate-limiting first step of the classic (neutral) bile-acid biosynthesis pathway -
    7-alpha-hydroxylation of cholesterol to 7-alpha-hydroxycholesterol - in the
    endoplasmic reticulum membrane, using heme iron and NADPH-derived electrons.
  molecular_function:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  directly_involved_in:
  - id: GO:0006699
    label: bile acid biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:11013305
    supporting_text: >-
      Human CYP7A, recombinantly expressed in Escherichia coli and in simian COS cells,
      showed 7alpha-hydroxylase activity toward both cholesterol
  - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
    supporting_text: >-
      Catalyzes the hydroxylation of carbon hydrogen bond at 7-alpha position of
      cholesterol, a rate-limiting step in cholesterol catabolism and bile acid
      biosynthesis
- description: >-
    Contribution of the same cholesterol 7-alpha-hydroxylase activity to cholesterol
    catabolism - conversion of cholesterol to bile acids is the major route of cholesterol
    elimination, of which CYP7A1 catalyses the rate-limiting step.
  molecular_function:
    id: GO:0008123
    label: cholesterol 7-alpha-monooxygenase activity
  directly_involved_in:
  - id: GO:0006707
    label: cholesterol catabolic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
    supporting_text: >-
      a rate-limiting step in cholesterol catabolism and bile acid biosynthesis
- description: >-
    Heme-iron cofactor binding required for the cytochrome P450 monooxygenase catalysis;
    CYP7A1 is a heme-thiolate P450 with Cys444 as the axial heme-iron ligand.
  molecular_function:
    id: GO:0020037
    label: heme binding
  supported_by:
  - reference_id: file:human/CYP7A1/CYP7A1-uniprot.txt
    supporting_text: 'Name=heme; Xref=ChEBI:CHEBI:30413'
proposed_new_terms: []
suggested_questions:
- question: >-
    Beyond transcriptional feedback (FXR/bile acids, HNF4alpha, glucose), is human CYP7A1
    activity subject to significant post-translational or allosteric regulation?
- question: >-
    What is the quantitative in vivo contribution of CYP7A1's oxysterol 7-alpha-hydroxylase
    activities (24S-hydroxycholesterol, 4-beta-hydroxycholesterol, 7-dehydrocholesterol
    oxidation) relative to its cholesterol 7-alpha-hydroxylation?
suggested_experiments:
- description: >-
    Reconstitute purified recombinant human CYP7A1 with cytochrome P450 reductase and
    measure steady-state kinetics across cholesterol and the physiological oxysterol
    substrates to rank in vivo relevance.
- description: >-
    Use isotope-labeled flux analysis in primary human hepatocytes (or CYP7A1-edited lines)
    to quantify the fraction of cholesterol catabolism proceeding through the
    CYP7A1-initiated classic pathway versus the acidic (CYP27A1/CYP7B1) pathway.