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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004082 bisphosphoglycerate mutase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/BPGM/BPGM-uniprot.txt Plays a major role in regulating hemoglobin oxygen affinity PMID:2542247 is a trifunctional enzyme which |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred cytosolic localization. BPGM is a soluble cytosolic enzyme of the erythrocyte, consistent with its role in glycolysis / the Rapoport-Luebering shunt. Reason: Correct core localization. Family members are cytosolic and BPGM is a soluble erythrocyte enzyme with no membrane or organelle-targeting features. Supporting Evidence: file:human/BPGM/BPGM-uniprot.txt Expressed in red blood cells. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | 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. Reason: This is an uninformative high-level parent of the specific molecular function GO:0004082, which is independently annotated. It adds no functional information. |
| GO:0004082 bisphosphoglycerate mutase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniProt/RHEA/EC 5.4.2.4) assertion of bisphosphoglycerate mutase activity, duplicating the IBA and experimental annotations for the same term. 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. Supporting Evidence: file:human/BPGM/BPGM-uniprot.txt controlling the levels of its allosteric effector 2,3- |
| GO:0004619 phosphoglycerate mutase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/BPGM/BPGM-uniprot.txt Also exhibits mutase (EC 5.4.2.11) |
| GO:0006096 glycolytic process | IEA GO_REF:0000120 | ACCEPT | 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. 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. |
| GO:0016868 intramolecular phosphotransferase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | 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). 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. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a large-scale interactome/affinity-purification study (WITH/FROM UniProtKB:P15259, PGAM2). This term conveys no specific molecular function. 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. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a high-throughput binary interactome map (HuRI; WITH/FROM UniProtKB:P15259, PGAM2). Uninformative as a molecular function. 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. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a proteome-scale affinity-purification network (BioPlex; WITH/FROM UniProtKB:P15259, PGAM2). Uninformative as a molecular function. 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. |
| GO:1901136 carbohydrate derivative catabolic process | TAS Reactome:R-HSA-6798335 | KEEP AS NON CORE | 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. 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. Supporting Evidence: Reactome:R-HSA-6798335 One of its functions is the isomerisation of 1,3-bisphosphoglycerate (1,3BPG) to 2,3-bisphosphoglycerate (2,3BPG) |
| GO:0004082 bisphosphoglycerate mutase activity | TAS Reactome:R-HSA-6798335 | ACCEPT | 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. 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. Supporting Evidence: Reactome:R-HSA-6798335 Bisphosphoglycerate mutase (BPGM) is an erythrocyte-specific trifunctional enzyme. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6798335 | ACCEPT | Summary: Reactome-traceable cytosolic localization, consistent with the soluble erythrocyte Rapoport-Luebering shunt. Reason: Correct core localization, corroborating the IBA cytosol annotation. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:23533145 exosome preparations were |
| GO:0005975 carbohydrate metabolic process | NAS PMID:2542247 Isolation, characterization, and structure of a mutant 89 Ar... | KEEP AS NON CORE | Summary: Author-stated (NAS) involvement in carbohydrate metabolism, reflecting BPGM's action on glycerate-phosphate intermediates of glycolysis / the Rapoport-Luebering shunt. Reason: A broad parent process; correct but less informative than the glycolytic process annotation. Kept as non-core. Supporting Evidence: PMID:2542247 is a trifunctional enzyme which |
| GO:0004082 bisphosphoglycerate mutase activity | TAS PMID:2542247 Isolation, characterization, and structure of a mutant 89 Ar... | ACCEPT | 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. 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. Supporting Evidence: PMID:2542247 displays synthase, mutase, and phosphatase activities. PMID:2542247 normal and that of the mutase 4.1%. |
| GO:0007585 respiratory gaseous exchange by respiratory system | TAS PMID:2542247 Isolation, characterization, and structure of a mutant 89 Ar... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/BPGM/BPGM-uniprot.txt Plays a major role in regulating hemoglobin oxygen affinity |
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Download this section (compressed HTML)Q: 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)?
Q: 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?
Experiment: 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.
Experiment: 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.
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