id: P51857
gene_symbol: AKR1D1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AKR1D1 (steroid 5-beta-reductase; 3-oxo-5-beta-steroid 4-dehydrogenase;
  Delta(4)-3-oxosteroid 5-beta-reductase; gene synonym SRD5B1) is a cytosolic
  aldo-keto reductase (EC 1.3.1.3) that catalyzes the NADPH-dependent
  stereospecific reduction of the C4-C5 (Delta4) double bond of 3-oxo-Delta4
  steroids to the 5-beta configuration. This reduction creates the cis-fused
  (5-beta) A/B ring junction that is characteristic of bile acids. In bile-acid
  biosynthesis AKR1D1 reduces the CYP7A1/CYP8B1 pathway intermediates
  7-alpha-hydroxy-4-cholesten-3-one and 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one
  to their 5-beta-cholestan-3-one products, an obligatory step in the conversion
  of cholesterol into the primary bile acids cholic acid and chenodeoxycholic
  acid. The enzyme also 5-beta-reduces a broad range of C18-C27 3-oxo-Delta4
  steroid hormones (including testosterone, progesterone, androstenedione,
  cortisol, cortisone, corticosterone and aldosterone), contributing to steroid
  hormone catabolism. AKR1D1 is highly expressed in liver. Loss-of-function
  variants cause congenital bile acid synthesis defect type 2 (CBAS2; AKR1D1
  deficiency), a neonatal cholestatic liver disease with jaundice and hepatic
  failure.
alternative_products:
- name: '1'
  id: P51857-1
- name: '2'
  id: P51857-2
  sequence_note: VSP_042901
- name: '3'
  id: P51857-3
  sequence_note: VSP_042913
existing_annotations:
- term:
    id: GO:0004032
    label: aldose reductase (NADPH) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Family-level phylogenetic (IBA) molecular-function call inherited from the
      aldo-keto reductase (AKR1) family. AKR1D1 is a steroid 5-beta-reductase,
      not an aldose reductase; it shares only ~50% sequence identity with human
      aldose reductase and does not have aldose reductase as its physiological
      function.
    action: MODIFY
    reason: >-
      This is an over-general family term. The informative, experimentally
      supported molecular function of AKR1D1 is Delta4-3-oxosteroid
      5beta-reductase activity (GO:0047787, EC 1.3.1.3). The IBA correctly places
      the protein in the AKR family but the specific activity should be used.
    proposed_replacement_terms:
    - id: GO:0047787
      label: Delta4-3-oxosteroid 5beta-reductase activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      - FUNCTIONAL_DIVERGENCE
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        single delta 4-3-oxosteroid 5
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        Catalyzes the stereospecific NADPH-dependent reduction of the
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic inference that AKR1D1 acts in the cytosol, consistent with the
      family being soluble cytosolic aldo-keto reductases and with direct
      experimental localization of AKR1D1 itself.
    action: ACCEPT
    reason: >-
      Cytosolic localization is directly supported by experimental data (HPA IDA,
      PMID:7508385 IDA) and by the UniProt subcellular location. This is the core
      compartment where AKR1D1 acts.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0016229
    label: steroid dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) molecular-function call placing AKR1D1 as a steroid
      dehydrogenase/reductase. AKR1D1 acts on steroid substrates via an
      NADPH-dependent oxidoreductase mechanism, so this parent term is correct
      but less specific than the 5-beta-reductase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but general parent of the specific molecular function. Retained as
      a valid broader classification; the specific Delta4-3-oxosteroid
      5beta-reductase activity (GO:0047787) is the core MF captured separately.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0008209
    label: androgen metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic inference of involvement in androgen metabolism. AKR1D1 can
      5-beta-reduce androgens such as testosterone and androstenedione in vitro,
      but the human enzyme has a considerably narrower steroid-hormone activity
      than its rodent orthologs and its physiological role is dominated by bile
      acid biosynthesis.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Androgen metabolism is a peripheral in vitro activity for the human enzyme,
      which the original characterization notes is much narrower than the rat
      enzyme and more important for bile acid biosynthesis. Not a core process.
    propagation_review:
      root_cause: NO_FAILURE_NON_CORE
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        more important for bile acid biosynthesis than for metabolism
- term:
    id: GO:0047086
    label: ketosteroid monooxygenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) family term for a ketosteroid monooxygenase activity.
      AKR1D1 is an NADPH-dependent reductase (it reduces a C=C double bond), not a
      monooxygenase, and no oxygen-incorporating monooxygenase activity is
      described for it.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Mechanistically inconsistent with AKR1D1, which is a 5-beta-reductase.
      Monooxygenase activity is an over-propagated family term not supported for
      this protein.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        Catalyzes the stereospecific NADPH-dependent reduction of the
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation of cytoplasmic localization from the UniProt
      Subcellular Location mapping, consistent with AKR1D1 being a soluble
      cytosolic enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but broader than cytosol; the more precise cytosol term (GO:0005829)
      is the core compartment and is separately supported experimentally.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to bile acid biosynthetic process via the
      AKR1D1-specific InterPro entry (IPR044483). This is the central biological
      process for AKR1D1.
    action: ACCEPT
    reason: >-
      Bile acid biosynthesis is the core physiological role of AKR1D1, supported
      by experimental (IDA PMID:7508385), Reactome (TAS) and InterPro (IEA)
      evidence.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        This cis-configuration is crucial for bile acid biosynthesis
- term:
    id: GO:0008106
    label: alcohol dehydrogenase (NADP+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA machine-learning electronic annotation to alcohol dehydrogenase
      (NADP+) activity. AKR1D1 catalyzes reduction of a C4-C5 carbon-carbon
      double bond of 3-oxo-Delta4 steroids, not oxidation/reduction of an
      alcohol/carbonyl; this generic AKR mechanistic label does not capture the
      double-bond reductase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Less informative and mechanistically imprecise for AKR1D1. The physiological
      reaction is NADPH-dependent Delta4 double-bond reduction (GO:0047787,
      EC 1.3.1.3), not alcohol dehydrogenase activity.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0008202
    label: steroid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation to the general steroid metabolic process, consistent
      with AKR1D1 acting on steroid substrates (bile acid intermediates and
      steroid hormones).
    action: ACCEPT
    reason: >-
      Correct broad biological-process classification. AKR1D1 metabolizes steroid
      substrates as part of bile acid biosynthesis and steroid hormone
      metabolism.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation to the root oxidoreductase activity term
      from AKR family signatures. AKR1D1 is an NADPH-dependent oxidoreductase, but
      this is the least specific possible MF.
    action: MODIFY
    reason: >-
      Too general. Should be replaced by the specific Delta4-3-oxosteroid
      5beta-reductase activity (GO:0047787).
    proposed_replacement_terms:
    - id: GO:0047787
      label: Delta4-3-oxosteroid 5beta-reductase activity
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        Catalyzes the stereospecific NADPH-dependent reduction of the
- term:
    id: GO:0032787
    label: monocarboxylic acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to monocarboxylic acid metabolic process,
      presumably inferred because bile acids are monocarboxylic acids. AKR1D1
      acts on steroid ring intermediates upstream of the fully formed bile acid
      carboxylate and does not itself metabolize the carboxylic acid moiety.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-general/indirect. AKR1D1's function is steroid Delta4 double-bond
      reduction; the monocarboxylic acid framing is a downstream consequence, not
      the enzyme's activity. Bile acid biosynthetic process (GO:0006699) captures
      the role more precisely.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        This cis-configuration is crucial for bile acid biosynthesis
- term:
    id: GO:0042445
    label: hormone metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to hormone metabolic process, reflecting that
      AKR1D1 can 5-beta-reduce steroid hormones. For the human enzyme this is a
      secondary activity relative to bile acid biosynthesis.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Peripheral for the human enzyme, whose steroid-hormone activity is narrower
      than the rodent ortholog and whose dominant role is bile acid biosynthesis.
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        more important for bile acid biosynthesis than for metabolism
- term:
    id: GO:0047787
    label: Delta4-3-oxosteroid 5beta-reductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (EC/Rhea-based) annotation to the specific molecular function of
      AKR1D1: Delta4-3-oxosteroid 5beta-reductase (EC 1.3.1.3). This is the core,
      informative molecular function, extensively supported experimentally by
      enzyme characterization and crystallography.
    action: ACCEPT
    reason: >-
      This is the defining molecular function of AKR1D1, matching EC 1.3.1.3 and
      the multiple curated Rhea catalytic-activity reactions in UniProt (reduction
      of 3-oxo-Delta4 steroids to the 5-beta configuration). Core function.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        Catalyzes the stereospecific NADPH-dependent reduction of the
    - reference_id: PMID:7508385
      supporting_text: >-
        single delta 4-3-oxosteroid 5
- term:
    id: GO:0072582
    label: 17-beta-hydroxysteroid dehydrogenase (NADP+) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Rhea-mapped electronic annotation (RHEA:53484, androst-4-ene-3,11,17-trione
      to 17beta-hydroxyandrost-4-ene-3,11-dione) inferred as a
      17-beta-hydroxysteroid dehydrogenase activity. This reflects one in vitro
      reaction; AKR1D1's characterized physiological activity is Delta4 5-beta
      double-bond reduction, not 17-beta-HSD chemistry.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      An automated Rhea mapping of a single side reaction; not the core or
      informative molecular function. The 5-beta-reductase activity (GO:0047787)
      is the physiologically relevant term.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Protein binding annotation from a high-throughput BioPlex 2.0 AP-MS
      interactome screen (interactor AKR1C1, UniProt Q04828). This is a
      proteome-scale physical interaction, not an informative molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" carries no functional information about AKR1D1 and is
      derived from a large-scale interactome dataset. Per curation guidelines this
      uninformative term is marked as over-annotated rather than retained as a
      function.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: >-
        affinity purification-mass spectrometry methodology to elucidate protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Protein binding annotation from the BioPlex 3.0 proteome-scale AP-MS
      interactome (interactor AKR1C1, UniProt Q04828). A high-throughput physical
      interaction rather than an informative molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare "protein binding" from a large-scale interactome dataset;
      marked as over-annotated per curation guidelines.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: >-
        The first, BioPlex 3.0, results from affinity purification
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193368
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation placing AKR1D1 in the bile acid and
      bile salt synthesis pathway via 7alpha-hydroxycholesterol. Core process.
    action: ACCEPT
    reason: >-
      Bile acid biosynthesis is the central role of AKR1D1, corroborated by
      experimental and InterPro evidence.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        This cis-configuration is crucial for bile acid biosynthesis
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193775
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation placing AKR1D1 in bile acid/bile salt
      synthesis via 24-hydroxycholesterol. Core process.
    action: ACCEPT
    reason: >-
      Consistent with the core bile acid biosynthetic role of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        This cis-configuration is crucial for bile acid biosynthesis
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193807
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable-author annotation placing AKR1D1 in bile acid/bile salt
      synthesis via 27-hydroxycholesterol. Core process.
    action: ACCEPT
    reason: >-
      Consistent with the core bile acid biosynthetic role of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        This cis-configuration is crucial for bile acid biosynthesis
- term:
    id: GO:0008106
    label: alcohol dehydrogenase (NADP+) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192033
  qualifier: enables
  review:
    summary: >-
      Reactome mechanistic molecular-function label attached to the AKR1D1-catalyzed
      reduction of 4-cholesten-7alpha-ol-3-one. The reaction reduces the steroid
      C4-C5 double bond; "alcohol dehydrogenase (NADP+)" is a generic AKR label
      that is less informative than the 5-beta-reductase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Imprecise MF for AKR1D1. The physiologically relevant activity is
      Delta4-3-oxosteroid 5beta-reductase (GO:0047787, EC 1.3.1.3).
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0008106
    label: alcohol dehydrogenase (NADP+) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192067
  qualifier: enables
  review:
    summary: >-
      Reactome mechanistic MF label for the AKR1D1-catalyzed reduction of
      4-cholesten-7alpha,12alpha-diol-3-one; generic AKR label less informative
      than the 5-beta-reductase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Imprecise MF; the physiological activity is Delta4-3-oxosteroid
      5beta-reductase (GO:0047787).
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0008106
    label: alcohol dehydrogenase (NADP+) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193746
  qualifier: enables
  review:
    summary: >-
      Reactome mechanistic MF label for the AKR1D1-catalyzed reduction of
      4-cholesten-7alpha,24(S)-diol-3-one; generic AKR label less informative than
      the 5-beta-reductase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Imprecise MF; the physiological activity is Delta4-3-oxosteroid
      5beta-reductase (GO:0047787).
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0008106
    label: alcohol dehydrogenase (NADP+) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193755
  qualifier: enables
  review:
    summary: >-
      Reactome mechanistic MF label for an AKR1D1-catalyzed 5-beta-reduction step
      in bile acid synthesis; generic AKR label less informative than the
      5-beta-reductase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Imprecise MF; the physiological activity is Delta4-3-oxosteroid
      5beta-reductase (GO:0047787).
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0008106
    label: alcohol dehydrogenase (NADP+) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193821
  qualifier: enables
  review:
    summary: >-
      Reactome mechanistic MF label for the AKR1D1-catalyzed reduction of
      4-cholesten-7alpha,12alpha,27-triol-3-one; generic AKR label less
      informative than the 5-beta-reductase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Imprecise MF; the physiological activity is Delta4-3-oxosteroid
      5beta-reductase (GO:0047787).
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0008106
    label: alcohol dehydrogenase (NADP+) activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193824
  qualifier: enables
  review:
    summary: >-
      Reactome mechanistic MF label for the AKR1D1-catalyzed reduction of
      4-cholesten-7alpha,27-diol-3-one; generic AKR label less informative than
      the 5-beta-reductase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Imprecise MF; the physiological activity is Delta4-3-oxosteroid
      5beta-reductase (GO:0047787).
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct assay (Human Protein Atlas immunofluorescence) localizing AKR1D1 to
      the cytosol. Consistent with the soluble cytosolic nature of the enzyme.
    action: ACCEPT
    reason: >-
      Cytosol is the core compartment for AKR1D1, supported by direct assay and
      by UniProt.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:7508385
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of AKR1D1 to the cytoplasm from the original
      cloning/expression study of the human enzyme.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but broader than cytosol; retained as non-core because the more
      precise cytosol term is the core compartment.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192033
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of AKR1D1 to the cytosol for the
      bile acid synthesis reduction reactions.
    action: ACCEPT
    reason: >-
      Consistent with the core cytosolic localization of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192067
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of AKR1D1 to the cytosol.
    action: ACCEPT
    reason: >-
      Consistent with the core cytosolic localization of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193746
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of AKR1D1 to the cytosol.
    action: ACCEPT
    reason: >-
      Consistent with the core cytosolic localization of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193755
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of AKR1D1 to the cytosol.
    action: ACCEPT
    reason: >-
      Consistent with the core cytosolic localization of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193821
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of AKR1D1 to the cytosol.
    action: ACCEPT
    reason: >-
      Consistent with the core cytosolic localization of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193824
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author localization of AKR1D1 to the cytosol.
    action: ACCEPT
    reason: >-
      Consistent with the core cytosolic localization of AKR1D1.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0005496
    label: steroid binding
  evidence_type: TAS
  original_reference_id: PMID:7508385
  qualifier: enables
  review:
    summary: >-
      Steroid binding molecular function, consistent with AKR1D1 binding its
      3-oxo-Delta4 steroid substrates in the active site (seen in multiple
      substrate co-crystal structures). This binding is part of, and subordinate
      to, the catalytic 5-beta-reductase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Steroid binding is a genuine molecular property (substrate binding) but is a
      component of the catalytic 5-beta-reductase function rather than an
      independent core function.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        C4-C5 double bond of bile acid intermediates and steroid hormones
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:7508385
  qualifier: located_in
  review:
    summary: >-
      Direct experimental localization of the human enzyme to the cytosol in the
      original cloning/expression study.
    action: ACCEPT
    reason: >-
      Core cytosolic localization, directly supported.
    supported_by:
    - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
      supporting_text: >-
        SUBCELLULAR LOCATION: Cytoplasm
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:7508385
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental demonstration that the expressed human enzyme has high
      5-beta-reductase activity toward the bile acid intermediates
      7alpha-hydroxy- and 7alpha,12alpha-dihydroxy-4-cholesten-3-one, and is more
      important for bile acid biosynthesis than for steroid hormone metabolism.
      This is the core process.
    action: ACCEPT
    reason: >-
      Directly demonstrated core biological process; the expressed enzyme reduces
      the key bile acid biosynthetic intermediates.
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        more important for bile acid biosynthesis than for metabolism
- term:
    id: GO:0006707
    label: cholesterol catabolic process
  evidence_type: IDA
  original_reference_id: PMID:7508385
  qualifier: involved_in
  review:
    summary: >-
      Bile acid biosynthesis is the major route of cholesterol catabolism, so
      AKR1D1 is generically associated with cholesterol catabolism. However AKR1D1
      does not act on cholesterol itself; it reduces 3-oxo-Delta4 ring
      intermediates several steps downstream.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Indirect/downstream framing. AKR1D1's direct substrates are 3-oxo-Delta4
      steroid intermediates, not cholesterol. Bile acid biosynthetic process
      (GO:0006699) is the precise term for its role.
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        more important for bile acid biosynthesis than for metabolism
- term:
    id: GO:0007586
    label: digestion
  evidence_type: IDA
  original_reference_id: PMID:7508385
  qualifier: involved_in
  review:
    summary: >-
      Bile acids produced downstream of AKR1D1 aid dietary lipid digestion, so the
      enzyme is indirectly linked to digestion. This is a distal physiological
      consequence, not a direct function of AKR1D1.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Too indirect. AKR1D1 acts in hepatic bile acid biosynthesis; digestion is a
      downstream consequence of bile acids, not an activity of the enzyme.
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        more important for bile acid biosynthesis than for metabolism
- term:
    id: GO:0008207
    label: C21-steroid hormone metabolic process
  evidence_type: IDA
  original_reference_id: PMID:7508385
  qualifier: involved_in
  review:
    summary: >-
      AKR1D1 can 5-beta-reduce C21 steroid hormones (e.g. cortisol) in vitro. In
      the original characterization this activity was small relative to the bile
      acid intermediate activity, and the human enzyme is narrower than the rat
      enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      A secondary in vitro activity for the human enzyme, subordinate to its core
      bile acid biosynthetic role.
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        small but significant 5 beta-reduction
- term:
    id: GO:0008209
    label: androgen metabolic process
  evidence_type: IDA
  original_reference_id: PMID:7508385
  qualifier: involved_in
  review:
    summary: >-
      AKR1D1 can 5-beta-reduce androgens (e.g. testosterone) in vitro, but in the
      original characterization no activity was seen toward androstenedione and
      the human enzyme's steroid-hormone activity is narrower than the rat enzyme
      and secondary to bile acid biosynthesis.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Peripheral in vitro activity for the human enzyme; not a core process.
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        more important for bile acid biosynthesis than for metabolism
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:7508385
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Direct experimental annotation (MGI) that AKR1D1 acts upstream of or within
      bile acid biosynthesis, based on the demonstrated reduction of bile acid
      intermediates. Core process.
    action: ACCEPT
    reason: >-
      Core biological process directly supported by the enzyme's demonstrated
      reduction of bile acid biosynthetic intermediates.
    supported_by:
    - reference_id: PMID:7508385
      supporting_text: >-
        more important for bile acid biosynthesis than for metabolism
core_functions:
- description: >-
    NADPH-dependent Delta4-3-oxosteroid 5beta-reductase (EC 1.3.1.3) that reduces
    the C4-C5 double bond of 3-oxo-Delta4 steroids to the 5-beta configuration,
    forming the cis-fused A/B ring junction. In bile acid biosynthesis it reduces
    7alpha-hydroxy- and 7alpha,12alpha-dihydroxy-4-cholesten-3-one to their
    5beta-cholestan-3-one products.
  molecular_function:
    id: GO:0047787
    label: Delta4-3-oxosteroid 5beta-reductase activity
  directly_involved_in:
  - id: GO:0006699
    label: bile acid biosynthetic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
    supporting_text: >-
      Catalyzes the stereospecific NADPH-dependent reduction of the
  - reference_id: PMID:7508385
    supporting_text: >-
      more important for bile acid biosynthesis than for metabolism
- description: >-
    Broad steroid 5beta-reductase acting on C18-C27 3-oxo-Delta4 steroid hormones
    (e.g. testosterone, progesterone, cortisol, cortisone), contributing to
    steroid hormone metabolism/catabolism as a cytosolic activity.
  molecular_function:
    id: GO:0047787
    label: Delta4-3-oxosteroid 5beta-reductase activity
  directly_involved_in:
  - id: GO:0008202
    label: steroid metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/AKR1D1/AKR1D1-uniprot.txt
    supporting_text: >-
      C4-C5 double bond of bile acid intermediates and steroid hormones
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  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:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 2.0 proteome-scale AP-MS interactome; source of a bare protein
      binding IPI (interactor AKR1C1). Correctly cited but low relevance to
      AKR1D1's molecular function.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 proteome-scale AP-MS interactome; source of a bare protein
      binding IPI (interactor AKR1C1). Correctly cited but low relevance to
      AKR1D1's molecular function.
- id: PMID:7508385
  title: Cloning and expression of cDNA of human delta 4-3-oxosteroid 5 beta-reductase
    and substrate specificity of the expressed enzyme.
  findings:
  - statement: >-
      The human enzyme catalyzes NADPH-dependent 5-beta reduction of the Delta4
      double bond of bile acid intermediates and steroid hormones, with high
      activity toward 7alpha-hydroxy- and 7alpha,12alpha-dihydroxy-4-cholesten-3-one
      and only small activity toward steroid hormones; it is more important for
      bile acid biosynthesis than for steroid hormone metabolism.
    supporting_text: >-
      more important for bile acid biosynthesis than for metabolism
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Seminal cloning/expression/characterization paper (abstract only in cache).
      Establishes the 5-beta-reductase activity, cytosolic localization, and the
      dominant bile acid biosynthetic role. Multiple experimental GOA annotations
      trace to it.
- id: Reactome:R-HSA-192033
  title: 4-cholesten-7alpha-ol-3-one is reduced to 5beta-cholestan-7alpha-ol-3-one
  findings: []
- id: Reactome:R-HSA-192067
  title: 4-cholesten-7alpha, 12alpha-diol-3-one is reduced to 5beta-cholesten-7alpha,
    12alpha-diol-3-one
  findings: []
- id: Reactome:R-HSA-193368
  title: Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
  findings: []
- id: Reactome:R-HSA-193746
  title: 4-cholesten-7alpha,24(S)-diol-3-one is reduced to 5beta-cholestan-7alpha,24(S)-diol-3-one
  findings: []
- id: Reactome:R-HSA-193755
  title: 'TODO: Fetch title'
  findings: []
- id: Reactome:R-HSA-193775
  title: Synthesis of bile acids and bile salts via 24-hydroxycholesterol
  findings: []
- id: Reactome:R-HSA-193807
  title: Synthesis of bile acids and bile salts via 27-hydroxycholesterol
  findings: []
- id: Reactome:R-HSA-193821
  title: 4-cholesten-7alpha,12alpha,27-triol-3-one is reduced to 5beta-cholestan-7alpha,12alpha,27-triol-3-one
  findings: []
- id: Reactome:R-HSA-193824
  title: 4-cholesten-7alpha,27-diol-3-one is reduced to 5beta-cholestan-7alpha,27-diol-3-one
  findings: []
- id: file:human/AKR1D1/AKR1D1-uniprot.txt
  title: UniProtKB entry P51857 (AKR1D1, human) - curated record
  findings: []