id: Q96AT9
gene_symbol: RPE
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RPE is human ribulose-5-phosphate 3-epimerase (EC 5.1.3.1), an enzyme of the
  non-oxidative branch of the pentose phosphate pathway. It catalyses the
  reversible epimerisation of D-ribulose 5-phosphate to D-xylulose 5-phosphate.
  Acting alongside ribose-5-phosphate isomerase (RPIA), it converts the
  ribulose-5-phosphate generated by the oxidative branch into the
  xylulose-5-phosphate and ribose-5-phosphate substrates used by transketolase
  and transaldolase, thereby linking the pentose phosphate pathway back to
  glycolysis and supplying pentoses for nucleotide biosynthesis. The enzyme is a
  cytosolic, metal-dependent (divalent cation, physiologically Fe2+) TIM-barrel
  epimerase that functions as a homodimer, with two aspartate residues carrying
  out the acid-base proton transfers of the epimerisation.
alternative_products:
- name: '1'
  id: Q96AT9-1
- name: '2'
  id: Q96AT9-2
  sequence_note: VSP_008317, VSP_008318
- name: '3'
  id: Q96AT9-3
  sequence_note: VSP_047117, VSP_008318
- name: '4'
  id: Q96AT9-4
  sequence_note: VSP_055265
- name: '5'
  id: Q96AT9-5
  sequence_note: VSP_047117
existing_annotations:
- term:
    id: GO:0004750
    label: D-ribulose-phosphate 3-epimerase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function of RPE: reversible epimerisation of D-ribulose
      5-phosphate to D-xylulose 5-phosphate (EC 5.1.3.1). The phylogenetic (IBA)
      call is fully consistent with direct human biochemical/structural data.
    action: ACCEPT
    reason: >-
      This is the defining activity of RPE, directly demonstrated for the human
      enzyme and conserved across the family. The same term is independently
      supported by IDA (PMID:20923965) and IEA (EC/RHEA mapping).
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: RPE functions in the PPP, catalyzing
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "Catalyzes the reversible epimerization of D-ribulose 5-"
- term:
    id: GO:0009052
    label: pentose-phosphate shunt, non-oxidative branch
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      RPE acts in the non-oxidative branch of the pentose phosphate pathway,
      the most specific and accurate biological-process term for this enzyme.
    action: ACCEPT
    reason: >-
      RPE converts ribulose-5-phosphate (from the oxidative branch) to
      xylulose-5-phosphate, one of the substrates for transketolase in the
      non-oxidative branch. This IBA term is the precise, correct process term.
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: RPE functions in the PPP, catalyzing
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Broad grouping term for carbohydrate metabolism. Correct but far less
      specific than the pentose-phosphate-shunt terms also annotated to RPE.
    action: KEEP_AS_NON_CORE
    reason: >-
      A high-level ancestor of the pentose phosphate pathway terms. Not wrong,
      but non-informative relative to GO:0009052; retained as non-core context.
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: RPE functions in the PPP, catalyzing
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      RPE is a soluble cytosolic enzyme; the pentose phosphate pathway operates
      in the cytosol. Correct subcellular localisation.
    action: ACCEPT
    reason: >-
      Consistent across IBA and TAS (Reactome) evidence and with the enzyme's
      role in cytosolic carbohydrate metabolism.
    supported_by:
    - reference_id: Reactome:R-HSA-71303
      supporting_text: Cytosolic ribulose-5-phosphate-3-epimerase (RPE)
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      RPE binds one divalent metal cation per subunit (physiologically Fe2+),
      required for catalysis. Metal-ion binding is an intrinsic part of the
      active site.
    action: ACCEPT
    reason: >-
      Supported by human structural/biochemical data showing an octahedrally
      coordinated Fe2+ in the active site and by the UniProt cofactor
      annotation (Fe2+, Mn2+, Zn2+, Co2+). Independently annotated by IDA.
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: octahedrally coordinated Fe(2+) ion
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: Binds 1 divalent metal cation per subunit. Active with Fe(2+),
        and
- term:
    id: GO:0004750
    label: D-ribulose-phosphate 3-epimerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core epimerase activity via EC 5.1.3.1 /
      RHEA:13677 / InterPro. Agrees with experimental and phylogenetic evidence.
    action: ACCEPT
    reason: >-
      The EC 5.1.3.1 and RHEA:13677 mappings correctly capture the demonstrated
      human enzymatic activity. Duplicate of the IDA/IBA GO:0004750 annotations.
    supported_by:
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "Reaction=D-ribulose 5-phosphate = D-xylulose 5-phosphate;"
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic assignment of the broad carbohydrate-metabolism
      term. Correct but non-specific.
    action: KEEP_AS_NON_CORE
    reason: >-
      A high-level ancestor of the pentose-phosphate-shunt terms; retained as
      non-core context, superseded in specificity by GO:0009052 / GO:0006098.
    supported_by:
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: Belongs to the ribulose-phosphate 3-epimerase family.
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment placing RPE in the pentose phosphate pathway.
      Correct; slightly less specific than the non-oxidative-branch term.
    action: ACCEPT
    reason: >-
      RPE is a bona fide PPP enzyme. This parent-level pathway term is accurate
      and independently supported by IDA (PMID:20923965).
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: RPE functions in the PPP, catalyzing
- term:
    id: GO:0016857
    label: racemase and epimerase activity, acting on carbohydrates and derivatives
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Grouping term for carbohydrate-acting racemases/epimerases. RPE is a
      carbohydrate epimerase, but the specific child term GO:0004750 is
      available and experimentally supported.
    action: MODIFY
    reason: >-
      GO:0016857 is a direct ancestor of the specific, demonstrated activity
      GO:0004750 (D-ribulose-phosphate 3-epimerase activity). The more specific
      term should be used for this well-characterised enzyme.
    proposed_replacement_terms:
    - id: GO:0004750
      label: D-ribulose-phosphate 3-epimerase activity
    supported_by:
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "Reaction=D-ribulose 5-phosphate = D-xylulose 5-phosphate;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from a high-throughput binary interactome screen
      (HuRI), reporting a heterotypic interaction with PLEKHF2 (Q9H8W4). The
      interaction is corroborated by UniProt (NbExp=3) but the term is
      uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare GO:0005515 conveys no functional
      information. The underlying PPI (RPE-PLEKHF2) is real but its biological
      significance for RPE is unknown; the annotation should not be treated as a
      molecular function of RPE.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "Q96AT9; Q9H8W4: PLEKHF2;"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Self-self interaction (Q96AT9-Q96AT9) detected in a large-scale
      yeast-two-hybrid interactome screen, reflecting the RPE homodimer.
    action: KEEP_AS_NON_CORE
    reason: >-
      Captures the biologically real homodimer, but the informative term for
      the quaternary structure is GO:0042803 (protein homodimerization
      activity), which is separately annotated. This identical-protein-binding
      IPI is a lower-value duplicate; retained as non-core.
    supported_by:
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20923965
  qualifier: enables
  review:
    summary: >-
      Self-interaction supported by the human structural study, which
      crystallised RPE as a dimer. Reflects the physiological homodimer.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real homodimer self-interaction, better represented by GO:0042803
      (protein homodimerization activity, also annotated from this same paper).
      Retained as non-core.
    supported_by:
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Self-self interaction detected in a proteome-scale binary interactome
      map, consistent with the RPE homodimer.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate homodimer self-interaction; the informative term is GO:0042803.
      Retained as non-core.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: a systematic map of ?14,000 high-quality human
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Self-self interaction detected in the HuRI binary interactome, consistent
      with the RPE homodimer.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate homodimer self-interaction; the informative term for the
      quaternary structure is GO:0042803. Retained as non-core.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer."
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      RPE was detected in a shotgun proteomic survey of exosomes from expressed
      prostatic secretions (~900 proteins identified). This is a bulk proteomic
      detection, not evidence of a functional extracellular localisation for
      this cytosolic enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Cytosolic metabolic enzymes are frequently reported in exosome/proteomic
      datasets as passengers. RPE's established localisation and function are
      cytosolic; the exosome detection does not indicate a biological role for
      RPE in the extracellular space.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: exosome samples, ~900 proteins were detected
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-199803
  qualifier: located_in
  review:
    summary: >-
      Reactome (author statement) localises RPE to the cytosol, where it
      catalyses the RU5P<->XY5P interconversion.
    action: ACCEPT
    reason: >-
      Consistent with the IBA cytosol annotation and with the enzyme's role in
      the cytosolic pentose phosphate pathway.
    supported_by:
    - reference_id: Reactome:R-HSA-199803
      supporting_text: Cytosolic ribulose-5-phosphate-3-epimerase (RPE)
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71303
  qualifier: located_in
  review:
    summary: >-
      Reactome (author statement) localises RPE to the cytosol for the
      RU5P->XY5P reaction, using Fe2+ as cofactor.
    action: ACCEPT
    reason: >-
      Consistent with all other cytosol annotations and with the cytosolic
      pentose phosphate pathway.
    supported_by:
    - reference_id: Reactome:R-HSA-71303
      supporting_text: Cytosolic ribulose-5-phosphate-3-epimerase (RPE)
- term:
    id: GO:0004750
    label: D-ribulose-phosphate 3-epimerase activity
  evidence_type: IDA
  original_reference_id: PMID:20923965
  qualifier: enables
  review:
    summary: >-
      Direct experimental demonstration of the epimerase activity on the human
      enzyme, including structures with substrate/product and mutagenesis of
      catalytic residues. This is the strongest evidence for the core function.
    action: ACCEPT
    reason: >-
      Liang et al. determined RPE structures bound to D-ribulose 5-phosphate and
      D-xylulose 5-phosphate and showed by mutagenesis (e.g. S10A) that specific
      residues are required for activity, directly establishing EC 5.1.3.1.
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: Ser-10 to alanine almost abolished the enzymatic activity
    - reference_id: PMID:20923965
      supporting_text: RPE functions in the PPP, catalyzing
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:20923965
  qualifier: involved_in
  review:
    summary: >-
      Broad carbohydrate-metabolism term supported by the direct enzymatic
      study. Correct but non-specific relative to the pentose-phosphate terms.
    action: KEEP_AS_NON_CORE
    reason: >-
      High-level ancestor of the pentose phosphate pathway process terms;
      retained as non-core context.
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: RPE functions in the PPP, catalyzing
- term:
    id: GO:0006098
    label: pentose-phosphate shunt
  evidence_type: IDA
  original_reference_id: PMID:20923965
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence places RPE in the pentose phosphate pathway, catalysing a
      key non-oxidative-branch step and contributing to the antioxidant response.
    action: ACCEPT
    reason: >-
      Experimentally supported; RPE is an integral PPP enzyme. Complements the
      more specific non-oxidative-branch IBA term (GO:0009052).
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: an important enzyme for cellular response against oxidative stress
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:20923965
  qualifier: enables
  review:
    summary: >-
      RPE functions as a homodimer; the human structural study crystallised the
      enzyme as a dimer and UniProt records the subunit structure as a homodimer.
      This is the informative molecular-function term for RPE self-association.
    action: ACCEPT
    reason: >-
      The homodimer is the biologically active form of RPE (also stated by
      Reactome). This is the correct, specific representation of the
      self-interactions captured more vaguely by the GO:0042802 IPIs.
    supported_by:
    - reference_id: file:human/RPE/RPE-uniprot.txt
      supporting_text: "SUBUNIT: Homodimer."
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IDA
  original_reference_id: PMID:20923965
  qualifier: enables
  review:
    summary: >-
      Direct structural demonstration of a catalytic divalent metal ion (Fe2+)
      in the active site of human RPE.
    action: ACCEPT
    reason: >-
      Liang et al. resolved an octahedrally coordinated Fe2+ buried in the
      active site and showed the enzyme uses Fe2+ for catalysis; UniProt records
      binding of one divalent cation per subunit.
    supported_by:
    - reference_id: PMID:20923965
      supporting_text: "(hRPE) uses Fe(2+) for catalysis"
    - reference_id: PMID:20923965
      supporting_text: octahedrally coordinated Fe(2+) ion
core_functions:
- description: >-
    Catalyses the reversible epimerisation of D-ribulose 5-phosphate to
    D-xylulose 5-phosphate in the non-oxidative branch of the pentose phosphate
    pathway, using an active-site divalent metal cation (physiologically Fe2+).
  molecular_function:
    id: GO:0004750
    label: D-ribulose-phosphate 3-epimerase activity
  directly_involved_in:
  - id: GO:0009052
    label: pentose-phosphate shunt, non-oxidative branch
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:20923965
    supporting_text: RPE functions in the PPP, catalyzing
  - reference_id: file:human/RPE/RPE-uniprot.txt
    supporting_text: "Reaction=D-ribulose 5-phosphate = D-xylulose 5-phosphate;"
- description: >-
    Binds one catalytic divalent metal cation (Fe2+, and probably Mn2+, Zn2+,
    Co2+) per subunit, required for the epimerase reaction.
  molecular_function:
    id: GO:0046872
    label: metal ion binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:20923965
    supporting_text: "(hRPE) uses Fe(2+) for catalysis"
  - reference_id: file:human/RPE/RPE-uniprot.txt
    supporting_text: Binds 1 divalent metal cation per subunit. Active with Fe(2+),
      and
- description: >-
    Self-associates into the catalytically active homodimer.
  molecular_function:
    id: GO:0042803
    label: protein homodimerization activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/RPE/RPE-uniprot.txt
    supporting_text: "SUBUNIT: Homodimer."
proposed_new_terms: []
suggested_questions:
- question: >-
    Does the RPE-PLEKHF2 (Q9H8W4) interaction reported in the binary interactome
    screens have any physiological relevance, or is it a screening artefact?
- question: >-
    Are any of the alternatively spliced isoforms (e.g. those missing the
    N-terminal region or catalytic residues) catalytically active or regulatory?
suggested_experiments:
- description: >-
    Metabolic flux analysis (e.g. 13C tracing through the non-oxidative PPP) in
    RPE-knockdown cells to quantify RPE's contribution to xylulose-5-phosphate
    and ribose-5-phosphate pools and to NADPH-dependent oxidative-stress
    resistance.
- description: >-
    Co-immunoprecipitation and orthogonal validation of the RPE-PLEKHF2
    interaction in relevant cell types to test its physiological significance.
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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale Y2H interactome screen (CCSB-HI1). Source of a self-self
      (identical protein binding) IPI reflecting the RPE homodimer; not
      functionally informative beyond the known homodimer.
- id: PMID:20923965
  title: 'Conversion of D-ribulose 5-phosphate to D-xylulose 5-phosphate: new insights
    from structural and biochemical studies on human RPE.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive structural and biochemical characterisation of human RPE:
      EC 5.1.3.1 activity, Fe2+ cofactor, TIM-barrel fold, catalytic aspartates,
      and mutagenesis. Supports the core MF, metal-binding, and PPP annotations.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Shotgun proteomics of prostatic-secretion exosomes (~900 proteins). Basis
      of the extracellular-exosome HDA annotation; a bulk detection, not
      evidence of functional extracellular localisation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale binary interactome map. Source of a self-self IPI
      reflecting the RPE homodimer.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome. Source of both a self-self IPI (homodimer) and a
      heterotypic RPE-PLEKHF2 (Q9H8W4) interaction; the latter underlies the
      bare protein-binding annotation and is corroborated by UniProt.
- id: Reactome:R-HSA-199803
  title: RPE dimers isomerize XY5P to RU5P
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction describing cytosolic RPE homodimer interconverting XY5P
      and RU5P; supports cytosol localisation and homodimer.
- id: Reactome:R-HSA-71303
  title: RPE dimers isomerise RU5P to XY5P
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction describing cytosolic RPE (Fe2+ cofactor) homodimer
      interconverting RU5P and XY5P; supports cytosol localisation, cofactor,
      and homodimer.
- id: file:human/RPE/RPE-uniprot.txt
  title: UniProt entry Q96AT9 (RPE_HUMAN)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt/Swiss-Prot record: FUNCTION, CATALYTIC ACTIVITY (EC 5.1.3.1,
      RHEA:13677), COFACTOR (divalent metal cations), SUBUNIT (homodimer), and
      the RPE-PLEKHF2 interaction.