id: P07738
gene_symbol: BPGM
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Bisphosphoglycerate mutase (BPGM) is the enzyme of the Rapoport-Luebering shunt, a branch
  of glycolysis that is prominently expressed in erythrocytes. It is a cytosolic homodimeric,
  trifunctional member of the cofactor-dependent (histidine) phosphoglycerate mutase family
  and uses a phospho-histidine catalytic intermediate. Its principal 2,3-bisphosphoglycerate
  synthase / bisphosphoglycerate mutase activity (EC 5.4.2.4) converts 1,3-bisphosphoglycerate
  to 2,3-bisphosphoglycerate (2,3-BPG); it additionally has a 2,3-BPG phosphatase activity that
  degrades 2,3-BPG to 3-phosphoglycerate and a weak phosphoglycerate mutase activity (EC 5.4.2.11).
  2,3-BPG is the major allosteric effector of hemoglobin: it binds preferentially to
  deoxyhemoglobin and lowers hemoglobin oxygen affinity, promoting oxygen delivery to tissues.
  By routing 1,3-bisphosphoglycerate through the shunt, BPGM also bypasses the ATP-generating
  phosphoglycerate kinase (PGK1) step of glycolysis. Loss-of-function causes bisphosphoglycerate
  mutase deficiency (familial erythrocytosis type 8), characterized by low 2,3-BPG, increased
  hemoglobin-oxygen affinity, and secondary erythrocytosis.
existing_annotations:
- term:
    id: GO:0004082
    label: bisphosphoglycerate mutase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred bisphosphoglycerate mutase activity. This is the principal,
      experimentally established molecular function of BPGM (EC 5.4.2.4; synthesis of
      2,3-bisphosphoglycerate from 1,3-bisphosphoglycerate) and the core function of the gene.
    action: ACCEPT
    reason: >-
      The IBA is correct and at the appropriate level of specificity. It matches the enzyme's
      defining catalytic activity, established biochemically and structurally in human BPGM.
    supported_by:
    - reference_id: file:human/BPGM/BPGM-uniprot.txt
      supporting_text: "Plays a major role in regulating hemoglobin oxygen affinity"
    - reference_id: PMID:2542247
      supporting_text: "is a trifunctional enzyme which"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred cytosolic localization. BPGM is a soluble cytosolic enzyme of the
      erythrocyte, consistent with its role in glycolysis / the Rapoport-Luebering shunt.
    action: ACCEPT
    reason: >-
      Correct core localization. Family members are cytosolic and BPGM is a soluble erythrocyte
      enzyme with no membrane or organelle-targeting features.
    supported_by:
    - reference_id: file:human/BPGM/BPGM-uniprot.txt
      supporting_text: "Expressed in red blood cells."
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based mapping to the root-level "catalytic activity" term. BPGM is an enzyme, so
      this is not wrong, but it is far less informative than the specific bisphosphoglycerate
      mutase activity already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an uninformative high-level parent of the specific molecular function GO:0004082,
      which is independently annotated. It adds no functional information.
- term:
    id: GO:0004082
    label: bisphosphoglycerate mutase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (UniProt/RHEA/EC 5.4.2.4) assertion of bisphosphoglycerate mutase activity,
      duplicating the IBA and experimental annotations for the same term.
    action: ACCEPT
    reason: >-
      Correct core molecular function, consistent with the RHEA:17765 / EC 5.4.2.4 reaction
      recorded in UniProt. Duplicate of the IBA/TAS annotations, which is acceptable.
    supported_by:
    - reference_id: file:human/BPGM/BPGM-uniprot.txt
      supporting_text: "controlling the levels of its allosteric effector 2,3-"
- term:
    id: GO:0004619
    label: phosphoglycerate mutase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (EC 5.4.2.11 / RHEA:15901) assertion of phosphoglycerate mutase activity. BPGM
      does exhibit a weak/secondary phosphoglycerate mutase activity in addition to its principal
      bisphosphoglycerate mutase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a genuine but secondary/minor activity of BPGM (UniProt records EC 5.4.2.11 in
      addition to the principal EC 5.4.2.4), so it is correct but not the core function.
    supported_by:
    - reference_id: file:human/BPGM/BPGM-uniprot.txt
      supporting_text: "Also exhibits mutase (EC 5.4.2.11)"
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assertion that BPGM is involved in the glycolytic process. BPGM operates in the
      Rapoport-Luebering shunt, a branch of glycolysis, acting on the glycolytic intermediate
      1,3-bisphosphoglycerate.
    action: ACCEPT
    reason: >-
      Correct: the Rapoport-Luebering shunt is a glycolytic branch and BPGM acts on/around the
      1,3-bisphosphoglycerate node of glycolysis (bypassing the PGK1 ATP-generating step). No
      more specific "2,3-BPG metabolic process" term exists in GO, so this is the best-fitting BP.
- term:
    id: GO:0016868
    label: intramolecular phosphotransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based mapping to intramolecular phosphotransferase activity, the parent class that
      captures the mutase/isomerase mechanism (phospho-group transfer within a molecule via a
      phospho-histidine intermediate).
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct branch and mechanistically accurate, but it is a less-informative parent of the
      specific bisphosphoglycerate mutase activity (GO:0004082) that is already annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from a large-scale interactome/affinity-purification study (WITH/FROM
      UniProtKB:P15259, PGAM2). This term conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "protein binding" (GO:0005515) is uninformative per curation guidelines. The interaction
      (with PGAM2, a paralogous phosphoglycerate mutase) is from a high-throughput interactome
      screen and does not establish a specific functional role; retained but flagged rather than
      used as a core function.
- 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 map (HuRI; WITH/FROM
      UniProtKB:P15259, PGAM2). Uninformative as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same rationale as the other protein-binding IPI annotations: GO:0005515 is uninformative and
      derives from a genome-scale interactome screen; kept but marked as over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from a proteome-scale affinity-purification network (BioPlex;
      WITH/FROM UniProtKB:P15259, PGAM2). Uninformative as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same rationale as the other protein-binding IPI annotations: GO:0005515 is uninformative and
      derives from a high-throughput interactome screen; kept but marked as over-annotation.
- term:
    id: GO:1901136
    label: carbohydrate derivative catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798335
  qualifier: involved_in
  review:
    summary: >-
      Reactome-traceable involvement in a carbohydrate-derivative catabolic process, reflecting
      BPGM consuming/isomerising the sugar-phosphate 1,3-bisphosphoglycerate (and the phosphatase
      breakdown of 2,3-BPG) within the Rapoport-Luebering shunt.
    action: KEEP_AS_NON_CORE
    reason: >-
      A defensible but broad process description of BPGM's action on phosphorylated glycerate
      intermediates; the more specific and central process is the glycolytic Rapoport-Luebering
      shunt (glycolytic process). Kept as non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-6798335
      supporting_text: "One of its functions is the isomerisation of 1,3-bisphosphoglycerate (1,3BPG)  to 2,3-bisphosphoglycerate (2,3BPG)"
- term:
    id: GO:0004082
    label: bisphosphoglycerate mutase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798335
  qualifier: enables
  review:
    summary: >-
      Reactome-traceable assertion of bisphosphoglycerate mutase activity (isomerisation of
      1,3-BPG to 2,3-BPG). This is the core molecular function of BPGM.
    action: ACCEPT
    reason: >-
      Correct core molecular function with a traceable Reactome reaction (BPGM dimer isomerises
      1,3BPG to 2,3BPG). Duplicate of the IBA/IEA annotations for GO:0004082, which is acceptable.
    supported_by:
    - reference_id: Reactome:R-HSA-6798335
      supporting_text: "Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific trifunctional enzyme."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798335
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable cytosolic localization, consistent with the soluble erythrocyte
      Rapoport-Luebering shunt.
    action: ACCEPT
    reason: >-
      Correct core localization, corroborating the IBA cytosol annotation.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of BPGM in urinary/prostatic-secretion exosome
      preparations. This is a proteome-inventory observation, not the functional site of BPGM,
      which acts as a soluble cytosolic enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Exosome/secretome mass-spec inventories frequently capture abundant cytosolic enzymes as
      passengers. There is no evidence that BPGM functions in the extracellular exosome; its
      catalytic role is cytosolic. Retained but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: "exosome preparations were"
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: NAS
  original_reference_id: PMID:2542247
  qualifier: involved_in
  review:
    summary: >-
      Author-stated (NAS) involvement in carbohydrate metabolism, reflecting BPGM's action on
      glycerate-phosphate intermediates of glycolysis / the Rapoport-Luebering shunt.
    action: KEEP_AS_NON_CORE
    reason: >-
      A broad parent process; correct but less informative than the glycolytic process
      annotation. Kept as non-core.
    supported_by:
    - reference_id: PMID:2542247
      supporting_text: "is a trifunctional enzyme which"
- term:
    id: GO:0004082
    label: bisphosphoglycerate mutase activity
  evidence_type: TAS
  original_reference_id: PMID:2542247
  qualifier: enables
  review:
    summary: >-
      Traceable assertion of bisphosphoglycerate mutase activity from a study characterizing a
      catalytically impaired human BPGM variant (89 Arg->Cys) with markedly reduced synthase and
      mutase activities, directly linking the protein to this activity.
    action: ACCEPT
    reason: >-
      Core molecular function, supported by biochemical characterization of the human enzyme and
      a disease-associated active-site variant. Duplicate of other GO:0004082 annotations, which
      is acceptable.
    supported_by:
    - reference_id: PMID:2542247
      supporting_text: "displays synthase, mutase, and phosphatase activities."
    - reference_id: PMID:2542247
      supporting_text: "normal and that of the mutase 4.1%."
- term:
    id: GO:0007585
    label: respiratory gaseous exchange by respiratory system
  evidence_type: TAS
  original_reference_id: PMID:2542247
  qualifier: involved_in
  review:
    summary: >-
      Traceable annotation to respiratory gaseous exchange by the respiratory system. BPGM does
      modulate systemic oxygen delivery by setting 2,3-BPG levels and thereby hemoglobin oxygen
      affinity, but this GO term denotes gas exchange by the respiratory (breathing) system
      (lungs), not the erythrocyte hemoglobin-affinity mechanism through which BPGM acts.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      BPGM's contribution to oxygen transport is via 2,3-BPG allosteric regulation of hemoglobin,
      not via respiratory-system gas exchange. The term is a broad/mismatched process for this
      enzyme; the oxygen-delivery role is better captured through its molecular function and the
      2,3-BPG glycolytic shunt. Retained but flagged as over-annotation.
    supported_by:
    - reference_id: file:human/BPGM/BPGM-uniprot.txt
      supporting_text: "Plays a major role in regulating hemoglobin oxygen affinity"
core_functions:
- description: >-
    Bisphosphoglycerate mutase / 2,3-bisphosphoglycerate synthase activity: BPGM isomerises the
    glycolytic intermediate 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate (2,3-BPG) in the
    erythrocyte Rapoport-Luebering shunt (and, at lower pH, degrades 2,3-BPG via its phosphatase
    activity). By controlling 2,3-BPG levels it sets hemoglobin oxygen affinity, promoting oxygen
    delivery to tissues, and it bypasses the ATP-generating PGK1 step of glycolysis.
  molecular_function:
    id: GO:0004082
    label: bisphosphoglycerate mutase activity
  directly_involved_in:
  - id: GO:0006096
    label: glycolytic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/BPGM/BPGM-uniprot.txt
    supporting_text: "Plays a major role in regulating hemoglobin oxygen affinity"
  - reference_id: Reactome:R-HSA-6798335
    supporting_text: "One of its functions is the isomerisation of 1,3-bisphosphoglycerate (1,3BPG)  to 2,3-bisphosphoglycerate (2,3BPG)"
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: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PAN-GO/GO_Central phylogenetic inference; supports the core bisphosphoglycerate mutase
      activity and cytosol annotations at the correct level of specificity.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- 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: >-
      High-throughput exosome proteome inventory; BPGM detected as an abundant cytosolic passenger,
      not evidence of extracellular-exosome function.
- id: PMID:2542247
  title: Isolation, characterization, and structure of a mutant 89 Arg
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Characterizes human BPGM as a trifunctional (synthase/mutase/phosphatase) enzyme and a
      disease-associated active-site variant with reduced synthase and mutase activities.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale interactome (BioPlex-type) study; source of a bare protein-binding IPI (with
      PGAM2), uninformative for specific molecular function.
- 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 map; source of a bare protein-binding IPI (with PGAM2), uninformative
      for specific 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 proteome-scale network; source of a bare protein-binding IPI (with PGAM2),
      uninformative for specific molecular function.
- id: Reactome:R-HSA-6798335
  title: BPGM dimer isomerises 1,3BPG to 2,3BPG
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction describing BPGM isomerising 1,3-BPG to 2,3-BPG, the allosteric hemoglobin
      effector; directly supports the core molecular function and biological process.
- id: file:human/BPGM/BPGM-uniprot.txt
  title: UniProt entry P07738 (PMGE_HUMAN), Bisphosphoglycerate mutase
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt curated record documenting the trifunctional activities (EC 5.4.2.4, EC 5.4.2.11),
      hemoglobin oxygen-affinity regulation via 2,3-BPG, homodimer, cytosolic erythrocyte
      expression, and ECYT8 disease association.
suggested_questions:
- question: >-
    What determines the in vivo balance between the synthase, mutase, and phosphatase activities
    of BPGM, and how is 2,3-BPG homeostasis regulated in erythrocytes under different physiological
    conditions (e.g., hypoxia, altitude, anemia)?
- question: >-
    Does the reported BPGM-PGAM2 interaction have any functional significance, or is it an
    artifact of high-throughput interactome screens between two closely related mutases?
suggested_experiments:
- description: >-
    Knockdown/knockout of BPGM in erythroid cells with metabolomic measurement of 2,3-BPG and
    quantification of the resulting shift in hemoglobin oxygen-affinity (P50) to confirm the
    gene-to-phenotype link.
  hypothesis: >-
    Loss of BPGM lowers erythrocyte 2,3-BPG and increases hemoglobin oxygen affinity.
- description: >-
    Structure-guided mutagenesis of active-site residues (e.g., His-11, His-89, Arg-90) to
    dissect the contributions of synthase vs mutase vs phosphatase activities to 2,3-BPG levels.
  hypothesis: >-
    Distinct active-site residues differentially control the synthase, mutase, and phosphatase
    activities that together set steady-state 2,3-BPG.