Affinage

BPGM

Bisphosphoglycerate mutase · UniProt P07738

Length
259 aa
Mass
30.0 kDa
Annotated
2026-06-09
90 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BPGM is a multifunctional erythroid-enriched enzyme that governs the Rapoport-Luebering shunt by producing 2,3-bisphosphoglycerate (2,3-BPG), the allosteric effector that lowers hemoglobin O2 affinity to drive tissue oxygenation (PMID:3023066, PMID:15054810). A single active site supports three interconvertible activities—2,3-BPG synthase, phosphoglycerate mutase, and 2,3-BPG phosphatase—whose balance is dictated by Gly13, which directs phosphoryl transfer to water versus carbohydrate substrate (PMID:8170953), while Cys22/Ser23 govern binding of the phosphatase activator 2-phosphoglycolate and Arg89 is required for monophosphoglycerate substrate binding and catalytic competence (PMID:9162026, PMID:2167078). Crystal structures resolve both an active-site and a dimer-interface binding site for 2-phosphoglycolate and reveal conformational non-equivalence between the two protomer active sites (PMID:35362470), and structures of clinical variants define the structural basis of enzyme deficiency (PMID:41354380). Loss-of-function mutations such as Arg89→Cys (Créteil I), a Créteil II frameshift, and Arg62Gln cause complete BPGM deficiency with markedly reduced 2,3-BPG, a left-shifted oxygen dissociation curve, and secondary erythrocytosis (PMID:1421379, PMID:15054810). In erythrocytes, BPGM activity is set by an adenosine→AMPK signaling axis acting downstream of the nucleoside transporter ENT1, the adenosine receptor ADORA2B, AMPD3, and S1P/PP2A signaling, all converging on AMPK to stimulate 2,3-BPG output and O2 delivery (PMID:32434995, PMID:34138843, PMID:37725437, PMID:32284030), and is suppressed when H2S drives BPGM relocalization to the membrane (PMID:33628390). Beyond O2 delivery, BPGM is expressed and functional in non-erythroid tissues including syncytiotrophoblast, distal nephron, astrocytes, and oocytes (PMID:16246416, PMID:39422260, PMID:36334804, PMID:40323314); through its product 2,3-BPG it maintains PGAM1 phosphorylation to limit 3-phosphoglycerate accumulation and serine biosynthetic flux (PMID:28805803), restrains glycolysis under hypoxia via HIF-1α/TET2/FIH-1 regulation (PMID:36334804), and acts as an NFAT5 transcriptional target coupling osmotic stress to HIF-1α (PMID:41741816). In cancer, BPGM promotes hepatocarcinogenesis through lactate-driven P300-mediated RET lactylation and macrophage M2 polarization (PMID:41514495) and restrains metastasis via a CDK1–EZH2–H3K27me3 axis that silences BBOX1 to suppress carnitine-dependent fatty acid oxidation (PMID:41875824).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1986 High

    Establishing the molecular identity of BPGM was the first step: cloning defined it as a single 258-residue multifunctional enzyme controlling 2,3-BPG metabolism with erythroid-restricted expression.

    Evidence cDNA cloning, cell-free translation, immunoprecipitation, and tryptic peptide sequencing of human reticulocyte mRNA

    PMID:3023066 PMID:6145409

    Open questions at the time
    • Did not resolve which residues mediate the three distinct catalytic activities
    • Tissue restriction later overturned by detection in non-erythroid tissues
  2. 1987 Medium

    Chromosomal mapping placed the gene at 7q22–q34, a prerequisite for linking the locus to disease alleles.

    Evidence In situ hybridization of a cDNA clone to metaphase chromosomes

    PMID:2824335

    Open questions at the time
    • No functional or regulatory information about the locus
    • Single method localization
  3. 1992 High

    Identifying the active-site determinants and the molecular basis of human BPGM deficiency connected specific residues to catalysis and disease phenotype.

    Evidence Site-directed mutagenesis of Arg89, plus molecular characterization of compound heterozygous Créteil I (Arg89Cys) and Créteil II (frameshift) alleles in a deficient patient

    PMID:1421379 PMID:2167078

    Open questions at the time
    • Did not explain how a single site partitions synthase/mutase/phosphatase activities
    • Structural consequence of mutations inferred, not visualized
  4. 1994 High

    Dissecting how one active site executes three reactions: Gly13 was shown to direct phosphoryl transfer toward water (phosphatase) versus carbohydrate (mutase/synthase), explaining the trifunctional behavior.

    Evidence Recombinant Gly13 mutants (Ser, Arg, Lys) assayed for synthase, mutase, and phosphatase activities

    PMID:8170953

    Open questions at the time
    • Did not address activator binding determinants
    • No structural visualization of the altered active site
  5. 1997 High

    Defining activator binding: Cys22 and Ser23 were identified as required for 2-phosphoglycolate-stimulated phosphatase activity, separating substrate binding from activator binding within the active site.

    Evidence Kinetic analysis (Ka, Km) of Cys22 and Ser23 mutants plus CD spectroscopy detecting 2,3-DPG-induced conformational change

    PMID:9162026

    Open questions at the time
    • Allosteric versus active-site location of the activator site not resolved until later crystallography
    • Structural basis of conformational change inferred from CD only
  6. 1998 High

    A pathophysiological inactivation mechanism was found: in vivo glycation at Lys158 near the substrate site abolishes BPGM activity in diabetic erythrocytes.

    Evidence Boronate affinity purification, activity assay, peptide sequencing, immunochemistry, and in vitro glycation of recombinant enzyme

    PMID:9832630

    Open questions at the time
    • Physiological consequence of impaired 2,3-BPG production in diabetes not quantified
    • Relative contribution of multiple glycation sites unresolved
  7. 2004 High

    A new deficiency allele (Arg62Gln) linked enzyme loss directly to reduced 2,3-BPG, left-shifted O2 dissociation, and secondary erythrocytosis, confirming the physiological role of BPGM in O2 release.

    Evidence Enzyme activity and 2,3-BPG assays, p50 measurement, DNA sequencing, and family study of a homozygous patient

    PMID:15054810

    Open questions at the time
    • Structural effect of Arg62Gln not visualized until later
    • Single family
  8. 2008 High

    The Rapoport-Luebering shunt was shown to be regulated beyond BPGM: MIPP1 provides a parallel 2,3-BPG phosphatase activity removing the 3-phosphate, expanding regulatory control of 2,3-BPG.

    Evidence Biochemical phosphatase assays, Dictyostelium Mipp1 genetic manipulation, and erythrocyte 2,3-BPG measurement

    PMID:18413611

    Open questions at the time
    • Relative in vivo flux through BPGM versus MIPP1 in human erythrocytes not fully quantified
    • MIPP1 is a separate enzyme, not a BPGM partner
  9. 2005 High

    BPGM was found to be active outside erythrocytes, in syncytiotrophoblast, overturning strict erythroid specificity and implying broader physiological roles.

    Evidence Western blot, immunohistochemistry, in situ hybridization, and cytochemical activity staining of human placenta

    PMID:16246416

    Open questions at the time
    • Functional importance of placental 2,3-BPG not directly tested by perturbation here
    • Did not address other non-erythroid tissues
  10. 2017 High

    A metabolic-regulatory role was established: BPGM-derived 2,3-BPG activates PGAM1 and limits 3-phosphoglycerate accumulation, thereby restraining serine biosynthetic flux.

    Evidence BPGM knockout cells, isotope-tracing metabolomics, PGAM1 phosphorylation assays, and growth measurements

    PMID:28805803

    Open questions at the time
    • Tissue contexts where this flux control dominates not defined
    • Did not link to organismal phenotype
  11. 2020 High

    Upstream signaling control of erythrocyte BPGM was defined: adenosine-sensing through ENT1 and ADORA2B and S1P/PP2A signaling converge on AMPK to activate BPGM and 2,3-BPG production for O2 delivery.

    Evidence Erythrocyte-specific SphK1, ENT1, and ADORA2B knockout mice with isotopic flux, metabolomics, pharmacology, and physiological/translational readouts

    PMID:32284030 PMID:32434995 PMID:34138843

    Open questions at the time
    • Direct biochemical link between AMPK and BPGM phosphorylation state not fully mapped
    • Whether non-erythroid BPGM uses the same axis untested
  12. 2020 High

    BPGM activity was shown to be physiologically consequential in disease and infection: a loss-of-function mouse mutation protects against cerebral malaria via altered RBC metabolism.

    Evidence BpgmL166P mutant mice, Plasmodium infection, parasitemia, survival, and RBC metabolic profiling

    PMID:32966787

    Open questions at the time
    • Human relevance of the protective phenotype not established
    • Mechanism of impaired parasite maturation only partially defined
  13. 2021 Medium

    A localization-based off-switch was identified: H2S enhances BPGM membrane anchoring, reducing cytosolic enzyme and lowering 2,3-BPG.

    Evidence CSE knockout mice with H2S donor rescue, membrane/cytosol fractionation, metabolomics, and p50 measurement

    PMID:33628390

    Open questions at the time
    • Molecular mechanism of membrane anchoring not defined
    • Single lab
  14. 2022 High

    Structural and regulatory understanding advanced: hypoxia-responsive BPGM/2,3-BPG suppresses glycolysis via HIF-1α/TET2/FIH-1 in astrocytes, and crystal structures revealed a dimer-interface activator site and conformational asymmetry between the two active sites.

    Evidence BPGM knockdown/overexpression in astrocytes with glycolytic readouts and HIF-1α/TET2/FIH-1 quantification; X-ray crystallography with 2-phosphoglycolate and kinetics

    PMID:35362470 PMID:36334804

    Open questions at the time
    • Astrocyte mechanism from a single lab at Medium confidence
    • Functional role of active-site asymmetry in vivo unresolved
  15. 2023 High

    The erythrocyte adenosine→AMPK pathway was extended to AMPD3 and connected to chronic kidney disease, placing BPGM downstream of ENT1→AMPD3→AMPK.

    Evidence ENT1 and AMPD3 knockout mice, two CKD models, isotopic adenosine flux, BPGM/AMPK assays, and human CKD validation

    PMID:37725437

    Open questions at the time
    • Direct AMPK-to-BPGM molecular coupling step still indirect
    • Therapeutic targeting in humans untested
  16. 2024 High

    A non-erythroid physiological role in kidney was established: distal nephron BPGM is required to restrain glycolysis and oxidative stress, with its loss causing rapid renal injury.

    Evidence Inducible tubular-specific Bpgm knockout mice, histology, proteomics, and in vitro osmotic-stress knockdown with ROS and apoptosis assays

    PMID:39422260

    Open questions at the time
    • Mechanistic link between distal-nephron BPGM loss and proximal tubular injury unclear
    • Whether 2,3-BPG mediates the renal effect not isolated
  17. 2025 High

    BPGM was shown to be required for oocyte maturation and fertility through control of glucose and central carbon metabolism, broadening its physiological reach.

    Evidence Bpgm knockout mice, oocyte maturation and fertility measurement, single-oocyte metabolomics, and gene expression profiling

    PMID:40323314

    Open questions at the time
    • Whether 2,3-BPG specifically mediates the oocyte phenotype not isolated
    • Meiotic gene changes mechanistically unexplained
  18. 2026 Medium

    Cancer-context roles were defined: BPGM drives hepatocarcinogenesis through lactate-mediated RET K549 lactylation and M2 macrophage polarization, while in other contexts it suppresses metastasis via a CDK1–EZH2–H3K27me3 axis silencing BBOX1, and is upregulated by HIF-1α in NAFLD steatosis.

    Evidence Hepatocyte-specific Bpgm knockout (DEN model), LC-MS/MS lactylation mapping, ubiquitination and macrophage co-culture assays; CDK1/ChIP/orthotopic Meldonium models; knockdown in HepG2, organoids, and HFD mice with pyruvate rescue

    PMID:41514495 PMID:41875824 PMID:42126781

    Open questions at the time
    • Pro- versus anti-tumor roles are context-dependent and not reconciled mechanistically
    • Metastasis-suppressor and NAFLD findings from single labs, not independently replicated
  19. 2026 Medium

    BPGM was linked to osmotic stress transcription as an NFAT5 target controlling HIF-1α, establishing a metabolic-epigenetic regulatory axis.

    Evidence RNA-seq of Bpgm knockdown under hypertonic stress, NFAT5 target gene analysis, promoter enrichment, and HIF-1α quantification

    PMID:41741816

    Open questions at the time
    • Mechanism by which a metabolic enzyme product controls NFAT5 target induction unclear
    • No genetic reconstitution; single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AMPK biochemically activates BPGM, and how a single trifunctional enzyme is partitioned between O2-delivery, central-carbon metabolic control, and the divergent pro-/anti-tumor roles across tissues, remains unresolved.
  • No demonstrated direct BPGM phosphorylation site for AMPK
  • Determinants of tissue-specific functional output of 2,3-BPG not defined
  • Reconciliation of oncogenic versus metastasis-suppressive roles missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0016787 hydrolase activity 3 GO:0016853 isomerase activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
PGAM1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 BPGM was cloned from human reticulocyte mRNA and shown to encode a 258-residue multifunctional enzyme controlling 2,3-bisphosphoglycerate (2,3-BPG) metabolism; cell-free translation confirmed the protein is synthesized at its mature molecular weight with tissue-specific expression (erythroid cells only), and the revised amino acid sequence was established by tryptic peptide analysis. cDNA cloning, expression vector (lambda gt11), cell-free translation, immunoprecipitation, HPLC tryptic peptide sequencing, Northern blot The EMBO journal High 3023066
1984 Cell-free translation of reticulocyte mRNA produced BPGM at its mature molecular weight (no precursor form), and BPGM mRNA represents ~0.1% of non-heme protein synthesis in reticulocytes but only ~0.01% in fetal liver; no BPGM synthesis was detected from non-erythroid tissue mRNA. Cell-free reticulocyte lysate translation, immunoprecipitation, PAGE, sucrose gradient sedimentation (12S mRNA) Biochemical and biophysical research communications Medium 6145409
1987 The human BPGM gene was mapped by in situ hybridization to chromosome 7, region 7q34–7q22. In situ hybridization with 1.1-kb cDNA clone to metaphase chromosomes Human genetics Medium 2824335
1990 Site-directed mutagenesis of BPGM demonstrated that Arg89 is essential for enzymatic function: Arg89→Cys, Arg89→Gly, and Arg89→Ser substitutions all reproduced the loss of activity seen in the natural BPGM Créteil I deficiency mutation. C-terminal residues 252–256 were also found important for function. Site-directed mutagenesis, expression in bacterial vector, activity assays Biomedica biochimica acta Medium 2167078
1992 Complete BPGM deficiency in a human patient resulted from compound heterozygosity: one allele carried a missense mutation (89 Arg→Cys, BPGM Créteil I) producing an inactive but immunologically detectable enzyme, and the other carried a frameshift (deletion of C205 or C206, BPGM Créteil II). This established that the Arg89→Cys mutation generates a catalytically inactive yet antigenically intact protein. PCR, allele-specific oligonucleotide hybridization, DNA sequencing, RT-PCR of erythrocyte mRNA Blood High 1421379
1992 A 3D structural model of human BPGM was built using the yeast monophosphoglycerate mutase (MPGM) crystal structure as framework. The model identified a cluster of positively charged residues (especially arginines) at the active site entrance proposed as a secondary binding site for polyanionic substrates; Cys20 was positioned as the residue responsible for sulfhydryl-reagent inactivation; dimerization and possible tetramerization interfaces were identified by analogy. Comparative structural modeling based on yeast MPGM crystal structure, energy minimization Biochimie Low 1387804
1994 Site-directed mutagenesis of the active-site residue Gly13 in human BPGM revealed its role in controlling the balance of catalytic activities: Gly13→Ser did not alter synthase activity but doubled mutase and halved phosphatase activities; Gly13→Arg enhanced phosphatase activity 28.6-fold while reducing synthase and mutase activities ~10-fold; Gly13→Lys gave a 6.5-fold phosphatase increase with similar synthase/mutase reduction. These results established Gly13 as critical for directing phosphoryl transfer to water (phosphatase) versus carbohydrate substrates. Site-directed mutagenesis, recombinant protein expression, enzymatic activity assays (synthase, mutase, phosphatase) Proceedings of the National Academy of Sciences of the United States of America High 8170953
1997 Site-directed mutagenesis of BPGM active-site residues showed that Cys22 is specifically required for 2-phosphoglycolate (the physiological phosphatase activator) binding: Cys22→Thr and Cys22→Ser mutations greatly reduced 2-phosphoglycolate-stimulated phosphatase activity and Ka without affecting synthase/mutase activities or Km for 2,3-DPG and 3-PG. Ser23 was shown to be necessary for binding both 3-PG and 2-phosphoglycolate. Arg89 was confirmed to be specifically involved in monophosphoglycerates binding but not in 2-phosphoglycolate binding. CD spectroscopy showed 2,3-DPG induces protein structural changes consistent with phosphorylation of the enzyme. Site-directed mutagenesis, kinetic assays (Ka, Km), CD spectroscopy The Journal of biological chemistry High 9162026
1998 BPGM is inactivated by glycation in vivo in diabetic patients. The enzyme purified from diabetic erythrocytes via boronate affinity chromatography showed the glycated fraction was completely inactive. The primary in vivo glycation site was identified as Lys158; in vitro glycation also occurred at Lys2, Lys4, Lys17, Lys42, and Lys196. Loss of activity appeared attributable to glycation at Lys158, located near the substrate binding site. Boronate affinity chromatography, enzyme activity assay, reverse-phase HPLC of lysyl-endopeptidase digests, amino acid sequencing, anti-hexitollysine IgG immunoreactivity, in vitro glycation of recombinant BPGM Journal of biochemistry High 9832630
2004 Erythrocytosis in a patient of Iranian Jewish heritage was caused by near-complete deficiency of BPGM enzyme activity (0.16 IU/g Hb vs. normal 4.13–5.43 IU/g Hb) due to homozygosity for the 185G→A (Arg62Gln) missense mutation in exon 2, resulting in markedly decreased 2,3-BPG (0.3 µmol/g Hb vs. normal 11.4–19.4), left-shifted oxygen dissociation curve (p50 = 19 mmHg), and secondary erythrocytosis. BPGM enzyme activity assay, 2,3-BPG measurement, DNA sequencing of BPGM exon 2, p50 measurement, family study American journal of hematology High 15054810
2005 BPGM is expressed and enzymatically active in the syncytiotrophoblast layer of human placenta (a non-erythroid tissue), where it synthesizes 2,3-BPG at the feto-maternal interface. This was unexpected as BPGM was previously considered erythroid-specific. Western blot, immunohistochemistry, in situ hybridization, cytochemical activity staining of placental extracts Placenta High 16246416
2008 The enzyme MIPP1 (multiple inositol polyphosphate phosphatase) was identified as an additional 2,3-BPG phosphatase in erythrocytes that removes the 3-phosphate from 2,3-BPG (distinct from BPGM which removes the 2-phosphate), thereby expanding the regulatory capacity of the Rapoport-Luebering shunt beyond BPGM alone. MIPP1 activity in erythrocytes was estimated to match BPGM phosphatase activity, and MIPP1 is active at 4°C (relevant to blood storage). Genetic manipulation of Mipp1 in Dictyostelium confirmed physiological regulation of 2,3-BPG. Biochemical phosphatase assay, genetic manipulation of Mipp1 in Dictyostelium, erythrocyte 2,3-BPG measurement, pH-dependent activity studies Proceedings of the National Academy of Sciences of the United States of America High 18413611
2014 QM/MM simulation of human BPGM revealed the reaction mechanisms of both phosphatase and synthase activities, including the free energy profiles and key active-site residues. The calculations predicted that synthase activity has a much lower energy barrier than phosphatase activity, consistent with experimental activity measurements. Quantum mechanics/molecular mechanics (QM/MM) simulation, metadynamics, umbrella sampling Physical chemistry chemical physics : PCCP Low 24441588
2017 BPGM controls the flux through the serine biosynthesis pathway via its product 2,3-BPG. 2,3-BPG is the primary histidine-phosphate donor that activates PGAM1 (phosphoglycerate mutase 1). When BPGM is knocked out, 1,3-BPG can directly phosphorylate PGAM1, but PGAM1 activity is reduced, causing 3-phosphoglycerate to accumulate and serine biosynthesis to increase. Thus BPGM normally limits 3-PG availability and serine synthesis flux. BPGM knockout cell lines, isotope tracing metabolomics, PGAM1 phosphorylation assays, growth rate measurements Nature chemical biology High 28805803
2020 In erythrocytes, sphingosine 1-phosphate (S1P) produced by SphK1 activates BPGM (and AMPK1α) by reducing ceramide/S1P ratio and inhibiting PP2A (protein phosphatase 2A), leading to increased 2,3-BPG production and enhanced O2 delivery. Erythrocyte-specific SphK1 knockout mice showed impaired BPGM activity and reduced 2,3-BPG, while AMPK agonists or PP2A inhibitors rescued 2,3-BPG levels. This defines a PP2A–AMPK1α–BPGM signaling axis in erythrocytes. Erythrocyte-specific SphK1 knockout mice, U-13C6 glucose isotope flux analysis, untargeted metabolomics, AMPK agonist/PP2A inhibitor pharmacology, translational validation in human CKD erythrocytes Circulation research High 32284030
2020 Maternal erythrocyte ENT1 (equilibrative nucleoside transporter 1) controls BPGM activity via AMPK: ENT1-dependent adenosine uptake regulates intracellular AMP/ATP ratio, which activates AMPK, which in turn activates BPGM to produce 2,3-BPG, enhancing O2 delivery to the placenta. Genetic ablation of maternal eENT1 reduced AMPK activation and BPGM activity, impairing placental oxygenation and causing fetal growth restriction. Erythrocyte-specific ENT1 knockout mice, isotopic adenosine flux, metabolomics, AMPK/BPGM activity measurements, placental HIF-1α quantification JCI insight High 32434995
2020 BPGM deficiency in mice (BpgmL166P loss-of-function mutation) protects against Plasmodium-induced cerebral malaria and severe malarial anemia. Protection involves two mechanisms: enhanced stress erythroid response to RBC loss and altered intracellular milieu of RBCs (increased oxyhemoglobin, reduced energy metabolism), which impairs Plasmodium maturation and replication. Murine genetic model (BpgmL166P), Plasmodium infection, parasitemia measurement, survival analysis, RBC metabolic profiling, oxyhemoglobin quantification Cell reports High 32966787
2021 Erythrocyte ADORA2B (adenosine A2B receptor) activates AMPK and BPGM to promote 2,3-BPG production and O2 delivery. Loss of erythrocyte-specific ADORA2B in mice reduced AMPK activation and BPGM activity, decreased 2,3-BPG, and accelerated age-related cognitive and hearing decline. Erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity were found to decline during normal aging. Erythrocyte-specific ADORA2B knockout mice, AMPK/BPGM activity assays, 2,3-BPG measurement, behavioral testing (spatial learning/memory), auditory brainstem response, aging time-course PLoS biology High 34138843
2021 H2S promotes hemoglobin (Hb) release from the erythrocyte membrane to the cytosol, consequently enhancing BPGM anchoring to the membrane. This mechanism reduces 2,3-BPG production by decreasing BPGM availability in the cytosol. CSE knockout mice showed elevated erythrocyte 2,3-BPG and increased p50, reversed by H2S donor treatment. CSE knockout mice, H2S donor (GYY4137) treatment, metabolomic profiling, p50 measurement, membrane/cytosol fractionation, cultured mouse and human erythrocytes Oxidative medicine and cellular longevity Medium 33628390
2022 Crystal structures of human BPGM in complex with the activator 2-phosphoglycolate (2-PG), with and without 3-phosphoglycerate, were solved at 2.25 Å and 2.48 Å resolution. Structures revealed: (1) a new 2-PG binding site at the dimer interface in addition to the active-site binding; (2) conformational non-equivalence of the two active sites, with one in an open conformation with disordered Arg100, Arg116, Arg117, and C-terminus. Kinetic data confirmed 2-PG binds both an allosteric/noncatalytic site and the active site. X-ray crystallography, kinetic enzyme assays Acta crystallographica. Section D, Structural biology High 35362470
2022 BPGM is expressed in astrocytes and is upregulated upon acute hypoxia. BPGM knockdown in hypoxic astrocytes promoted glycolysis (increased lactate, glycolytic gene expression), while BPGM overexpression or 2,3-DPG addition to normoxic cells downregulated glycolytic genes. Mechanistically, BPGM/2,3-DPG suppressed glycolysis by negatively regulating HIF-1α and TET2, while increasing FIH-1 expression. BPGM knockdown (siRNA) and overexpression in HEB astrocyte cells, lactate measurement, glycolytic gene expression (qPCR/Western), HIF-1α/FIH-1/TET2 protein quantification, in vivo hypoxia model Brain research bulletin Medium 36334804
2023 Erythrocyte ENT1-AMPD3 axis controls BPGM activation: ENT1-mediated adenosine uptake generates AMP to activate AMPK, which then activates BPGM to produce 2,3-BPG and enhance O2 delivery. Loss of eENT1 abolishes AMPK and BPGM activation, reducing 2,3-BPG. Conversely, AMPD3 knockout preserves the adenine nucleotide pool, inducing AMPK-BPGM activation and protecting against CKD. This places BPGM downstream of ENT1→AMPD3→AMPK in erythrocytes. Erythrocyte-specific ENT1 and global AMPD3 knockout mice, two CKD models (Ang II and UUO), isotopic adenosine flux, metabolomics, AMPK/BPGM activity assays, translational human CKD studies Journal of the American Society of Nephrology : JASN High 37725437
2024 BPGM is expressed in the distal nephron of the kidney (absent from proximal tubules). Inducible tubular-specific Bpgm knockout caused rapid kidney injury within 4 days (proximal tubular damage and tubulointerstitial fibrosis). Knockdown in vitro under osmotic stress led to enhanced glycolysis, decreased ROS elimination capacity, and increased apoptosis. Proteomics revealed involvement of BPGM in glycolysis, oxidative stress response, and inflammation pathways, establishing a non-erythroid physiological role for BPGM in kidney metabolism. Doxycycline-inducible tubular-specific Bpgm knockout mice, histology, immunofluorescence, proteomics, in vitro Bpgm knockdown under osmotic stress, ROS measurement, apoptosis assay Acta physiologica (Oxford, England) High 39422260
2025 In erythrocytes of longevity individuals, increased BPGM and reduced MFSD2B protein levels collaboratively elevate intracellular S1P, promote GAPDH release from the membrane to the cytosol, and shift glucose metabolism toward the Rapoport-Luebering Shunt to increase 2,3-BPG production and O2 delivery. This BPGM–MFSD2B axis is associated with youthful erythrocyte O2 release function. Western blot for BPGM and MFSD2B protein quantification, untargeted erythrocyte metabolomics, 2,3-BPG and S1P measurement, GAPDH membrane/cytosol fractionation, cohort studies Aging cell Medium 39924931
2025 Crystal structures of human BPGM clinical variants (Arg62Gln, Arg90Cys, Arg90His, Gln102Lys) and a citrate-bound BPGM structure were solved, revealing the structural basis of BPGM deficiency mutations and identifying a citrate-binding mode associated with open/closed conformational changes linked to enzyme activity. X-ray crystallography of recombinant BPGM variants International journal of biological macromolecules High 41354380
2026 BPGM is a transcriptional target of NFAT5 induced under hypertonic conditions; BPGM depletion impairs induction of canonical NFAT5 target genes. BPGM regulates HIF-1α expression downstream of NFAT5, establishing a hierarchical NFAT5→BPGM→HIF-1α regulatory axis in osmotic stress response. Promoter analysis linked NFAT5/BPGM co-regulated genes to CpG islands and GC-rich elements, supporting metabolic-epigenetic coupling. RNA-seq (Bpgm knockdown vs. control under osmotic stress), NFAT5 target gene expression analysis, promoter enrichment analysis, HIF-1α quantification, in vitro hypertonic stress model Cellular and molecular life sciences : CMLS Medium 41741816
2026 In hepatocellular carcinoma (HCC), BPGM promotes lactate accumulation and P300-mediated lactylation of RET proto-oncogene at Lys549 (K549), which competitively inhibits RET ubiquitination and prevents its degradation, stabilizing RET protein. BPGM also promotes M2 polarization of tumor-associated macrophages via lactate secretion. Hepatocyte-specific Bpgm knockout significantly attenuated DEN-induced HCC development in mice. LC-MS/MS identification of RET K549 lactylation, hepatocyte-specific Bpgm knockout mice (DEN model), BPGM overexpression in HCC cells, single-cell RNA-seq, spatial transcriptomics, proliferation/migration assays, macrophage co-culture, ubiquitination assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 41514495
2026 BPGM acts as a metastasis suppressor by triggering CDK1-T14 phosphorylation-dependent assembly of an EZH2-H3K27me3 repressor complex that silences BBOX1 (γ-butyrobetaine hydroxylase, rate-limiting enzyme in carnitine biosynthesis), thereby suppressing carnitine-dependent fatty acid oxidation in metastatic cells. Hypoxia-mediated KDM4A-H3K9me3 cascade inactivates this checkpoint. 2,3-BPG levels predict metastatic virulence. Pharmacological BBOX1 inhibition with Meldonium recapitulated BPGM-mediated suppression in orthotopic models. High-resolution metabolomics, CDK1 phosphorylation assays, ChIP for EZH2/H3K27me3, BBOX1 expression assays, orthotopic tumor models with Meldonium treatment, KDM4A/H3K9me3 analyses Neoplasia (New York, N.Y.) Medium 41875824
2026 In nonalcoholic fatty liver disease (NAFLD), BPGM is upregulated by HIF-1α and promotes hepatic steatosis by altering glycolysis/gluconeogenesis and increasing pyruvate levels. BPGM knockdown in HepG2 cells, liver organoids, and HFD-fed mice attenuated lipid accumulation, cellular injury, and oxidative stress. Pyruvate addition reversed the protective effects of BPGM knockdown. BPGM knockdown (siRNA) in HepG2 cells, liver organoids (FFA model), and HFD mouse model; metabolomics, lipid staining, oxidative stress assays, HIF-1α manipulation Human cell Medium 42126781
2025 BPGM deletion in mouse oocytes (Bpgm knockout) significantly reduced the rate of oocyte maturation and mouse fertility (fewer pups per litter), accompanied by altered expression of meiosis-related genes and genes in glycolysis, TCA cycle, and pentose phosphate pathway. Single-oocyte metabolomics by nano-electrospray ionization MS showed that BPGM deficiency impaired glucose metabolism pathways, tyrosine metabolism, and amino acid biosynthesis in oocytes. Bpgm knockout mice, oocyte maturation rate assay, fertility measurement, single-cell metabolomics (induced nanoelectrospray-ionization MS), gene expression profiling Molecular human reproduction High 40323314

Source papers

Stage 0 corpus · 90 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. The Lancet. Respiratory medicine 485 28864056
2004 Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Molecular and cellular biology 307 15199147
2013 Genetic basis of congenital erythrocytosis: mutation update and online databases. Human mutation 103 24115288
2016 Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. Haematologica 75 27651169
2017 Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate. Nature chemical biology 66 28805803
2020 Erythrocyte Metabolic Reprogramming by Sphingosine 1-Phosphate in Chronic Kidney Disease and Therapies. Circulation research 58 32284030
1986 Molecular cloning and sequencing of the human erythrocyte 2,3-bisphosphoglycerate mutase cDNA: revised amino acid sequence. The EMBO journal 47 3023066
2008 Dephosphorylation of 2,3-bisphosphoglycerate by MIPP expands the regulatory capacity of the Rapoport-Luebering glycolytic shunt. Proceedings of the National Academy of Sciences of the United States of America 45 18413611
2020 Analysis of plasma metabolic profile, characteristics and enzymes in the progression from chronic hepatitis B to hepatocellular carcinoma. Aging 43 32701483
2018 Genetic basis of congenital erythrocytosis. International journal of laboratory hematology 41 29741264
2018 Genotype-Phenotype Correlation of Hereditary Erythrocytosis Mutations, a single center experience. American journal of hematology 41 29790589
2006 Maternal housekeeping proteins translated during bovine oocyte maturation and early embryo development. Proteomics 39 16739132
2004 Erythrocytosis due to bisphosphoglycerate mutase deficiency with concurrent glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. American journal of hematology 38 15054810
2005 Novel placental expression of 2,3-bisphosphoglycerate mutase. Placenta 31 16246416
1992 Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency. Blood 31 1421379
2013 [Differential expression of genes that encode glycolysis enzymes in kidney and lung cancer in humans]. Genetika 28 24450150
2023 Erythrocyte ENT1-AMPD3 Axis is an Essential Purinergic Hypoxia Sensor and Energy Regulator Combating CKD in a Mouse Model. Journal of the American Society of Nephrology : JASN 24 37725437
2021 Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming. PLoS biology 22 34138843
2022 Screening of Potential Biomarkers in the Peripheral Serum for Steroid-Induced Osteonecrosis of the Femoral Head Based on WGCNA and Machine Learning Algorithms. Disease markers 20 35154510
2020 Maternal erythrocyte ENT1-mediated AMPK activation counteracts placental hypoxia and supports fetal growth. JCI insight 19 32434995
1987 Chromosomal assignment of the human 2,3-bisphosphoglycerate mutase gene (BPGM) to region 7q34----7q22. Human genetics 18 2824335
1998 Human erythrocyte bisphosphoglycerate mutase: inactivation by glycation in vivo and in vitro. Journal of biochemistry 17 9832630
2020 Erythrocytosis: genes and pathways involved in disease development. Blood transfusion = Trasfusione del sangue 16 33370224
2020 Cardiac Transcriptome Analysis Reveals Nr4a1 Mediated Glucose Metabolism Dysregulation in Response to High-Fat Diet. Genes 15 32610475
2021 Differential proteomic analysis of children infected with respiratory syncytial virus. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 14 33656056
1987 Bisphosphoglycerate mutase and pyruvate kinase activities during maturation of reticulocytes and ageing of erythrocytes. Bioscience reports 14 2820524
2025 Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures. Aging cell 13 39924931
2024 Alteration in the number, morphology, function, and metabolism of erythrocytes in high-altitude polycythemia. Frontiers in physiology 13 38426208
2023 Muscle transcriptome analysis provides new insights into the growth gap between fast- and slow-growing Sinocyclocheilus grahami. Frontiers in genetics 13 37538358
2021 Hydrogen Sulfide Is a Regulator of Hemoglobin Oxygen-Carrying Capacity via Controlling 2,3-BPG Production in Erythrocytes. Oxidative medicine and cellular longevity 13 33628390
2014 Hereditary erythrocytosis, thrombocytosis and neutrophilia. Best practice & research. Clinical haematology 13 25189721
2024 Beyond hemoglobin: Critical role of 2,3-bisphosphoglycerate mutase in kidney function and injury. Acta physiologica (Oxford, England) 11 39422260
2021 Toward the assembly and characterization of an encoded library hit confirmation platform: Bead-Assisted Ligand Isolation Mass Spectrometry (BALI-MS). Bioorganic & medicinal chemistry 11 34000509
1994 A recombinant bisphosphoglycerate mutase variant with acid phosphatase homology degrades 2,3-diphosphoglycerate. Proceedings of the National Academy of Sciences of the United States of America 11 8170953
2022 Black phosphorus nanoparticles for dual therapy of non-small cell lung cancer. Journal of drug targeting 10 35078385
2022 Enhanced BPGM/2,3-DPG pathway activity suppresses glycolysis in hypoxic astrocytes via FIH-1 and TET2. Brain research bulletin 10 36334804
2021 Identification of Variants Associated With Rare Hematological Disorder Erythrocytosis Using Targeted Next-Generation Sequencing Analysis. Frontiers in genetics 10 34349782
1984 Synthesis and levels of organic phosphates in erythrocytes during avian development: specific formation of BPG and IP5 in two distinct populations from young chicks. Cell biochemistry and function 10 6097374
2024 The difference between young and older ducks: Amino acid, free fatty acid, nucleotide compositions and breast muscle proteome. Food chemistry: X 9 39810946
2023 Proteomics analyses of acute kidney injury biomarkers in a rat exertional heat stroke model. Frontiers in physiology 9 37378075
2023 Identification of cuproptosis-related molecular subtypes as a biomarker for differentiating active from latent tuberculosis in children. BMC genomics 9 37393262
2021 Involvement of glycolysis activation in flatfish sexual size dimorphism: Insights from transcriptomic analyses of Platichthys stellatus and Cynoglossus semilaevis. Comparative biochemistry and physiology. Part D, Genomics & proteomics 9 33930775
2021 Dysregulation of bisphosphoglycerate mutase during in vitro maturation of oocytes. Journal of assisted reproduction and genetics 9 34052998
1997 Critical role of human bisphosphoglycerate mutase Cys22 in the phosphatase activator-binding site. The Journal of biological chemistry 9 9162026
1984 Cell-free translation of messenger RNA for human bisphosphoglyceromutase. Biochemical and biophysical research communications 9 6145409
2021 FNDC3B and BPGM Are Involved in Human Papillomavirus-Mediated Carcinogenesis of Cervical Cancer. Frontiers in oncology 8 34976823
2020 Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia. Cell reports 8 32966787
2023 Analysis of the role of glucose metabolism-related genes in dilated cardiomyopathy based on bioinformatics. Journal of thoracic disease 7 37559624
2022 Heterozygosity for bisphosphoglycerate mutase deficiency expressing clinically as congenital erythrocytosis: A case series and literature review. British journal of haematology 7 36177683
2019 Algorithmic evaluation of hereditary erythrocytosis: Pathways and caveats. International journal of laboratory hematology 7 31069987
1992 Structural modeling of the human erythrocyte bisphosphoglycerate mutase. Biochimie 7 1387804
2023 Biphosphoglycerate Mutase: A Novel Therapeutic Target for Malaria? Transfusion medicine reviews 6 37827586
2022 Molecular insight into 2-phosphoglycolate activation of the phosphatase activity of bisphosphoglycerate mutase. Acta crystallographica. Section D, Structural biology 6 35362470
2020 Physiological and oxidative stress responses to intermittent hypoxia training in Sprague Dawley rats. Experimental lung research 6 32930002
2014 Insights into the phosphatase and the synthase activities of human bisphosphoglycerate mutase: a quantum mechanics/molecular mechanics simulation. Physical chemistry chemical physics : PCCP 6 24441588
2022 Moxibustion attenuates inflammation and alleviates axial spondyloarthritis in mice: Possible role of APOE in the inhibition of the Wnt pathway. Journal of traditional and complementary medicine 4 36081820
2009 Placental expression of 2,3 bisphosphoglycerate mutase in IGF-II knock out mouse: correlation of circulating maternal 2,3 bisphosphoglycerate and fetal growth. Placenta 4 19733906
2025 Transcriptome Insights into Protective Mechanisms of Ferroptosis Inhibition in Aortic Dissection. International journal of molecular sciences 3 40362577
2024 The differential regulation of placenta trophoblast bisphosphoglycerate mutase in fetal growth restriction: preclinical study in mice and observational histological study of human placenta. eLife 3 38314803
2016 A Novel Hemoglobin Variant Associated with Congenital Erythrocytosis: Hb Seoul [β86(F2)Ala→Thr] (HBB:c.259G>A). Annals of clinical and laboratory science 3 27312559
1990 Natural and artificial mutants of the human 2,3-bisphosphoglycerate as a tool for the evaluation of structure-function relationships. Biomedica biochimica acta 3 2167078
2025 Human Peripheral Blood Leukocyte Transcriptome-Based Aging Clock Reveals Acceleration of Aging by Bacterial or Viral Infections. The journals of gerontology. Series A, Biological sciences and medical sciences 2 40089807
2025 Gluconeogenesis related gene signatures as biomarkers for nonspecific orbital inflammation. Scientific reports 2 40595959
2024 Bisphosphoglycerate mutase predicts myocardial dysfunction and adverse outcome in sepsis: an observational cohort study. BMC infectious diseases 2 38326761
2022 Diagnosis and genetic analysis of polycythemia in children and a novel EPAS1 gene mutation. Pediatrics and neonatology 2 36002380
1997 New procedures to measure synthase and phosphatase activities of bisphosphoglycerate mutase. Interest for development of therapeutic drugs. Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie 2 9099261
2026 BPGM shapes NFAT5-driven cellular responses. Cellular and molecular life sciences : CMLS 1 41741816
2025 Study on the Protective Effect of Methyl Rosmarinate on Hypoxic Mice and Their Erythrocytes. Drug design, development and therapy 1 40303914
2025 Identification and validation of lactate-related gene signatures in endometriosis for clinical evaluation and immune characterization by WGCNA and machine learning. Frontiers in cell and developmental biology 1 41127572
2025 New human bisphosphoglycerate mutase structures provide insights into the structural basis of BPGM deficiency and citrate inhibition. International journal of biological macromolecules 1 41354380
2023 Fuzzy optimization for identifying antiviral targets for treating SARS-CoV-2 infection in the heart. BMC bioinformatics 1 37759157
2022 Bcl11a and the Correlated Key Genes Ascribable to Globin Switching: An In-silico Study. Cardiovascular & hematological disorders drug targets 1 35718959
1998 An enzyme-linked immunosorbent assay and reference ranges for bisphosphoglycerate mutase in human erythrocytes. Journal of clinical laboratory analysis 1 9773955
2026 Hepatocyte BPGM Induces RET Lactylation and Macrophage Reprogramming to Promote Tumorigenesis in Hepatocellular Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41514495
2026 SIAH2-WNK1 Signaling Drives Glycolytic Metabolism and Therapeutic Resistance in Colorectal Cancer. International journal of molecular sciences 0 41596707
2026 Genome-wide association study reveals acute mountain sickness susceptibility in Chinese population. Molecular genetics and genomics : MGG 0 41686271
2026 Photoacoustic Imaging of Muscle Tissue Oxygenation as a Noninvasive Biomarker in Mouse Models of Sickle Cell Disease. Molecular imaging and biology 0 41811585
2026 BPGM as an intrinsic brake to constrain metastasis through phospho-epigenetic-mediated carnitine biosynthesis suppression. Neoplasia (New York, N.Y.) 0 41875824
2026 Diabetes affects the composition of the respiratory tract microbiome and transcriptome in patients with viral pneumonia. Microbiology spectrum 0 41940665
2026 2,3-Bisphosphoglycerate Mutase (BPGM), a Metabolic Player Shaping Stress-Adaptive Transcriptional States in Clear Cell Renal Cell Carcinoma. Cells 0 41972721
2026 Identification and Screening of Lactate-Related Genes as Molecular Markers for Early Diagnosis of Steroid-Induced Osteonecrosis of the Femoral Head. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41982156
2026 Bisphosphoglycerate mutase is involved in glucose metabolism and progression of nonalcoholic fatty liver disease based on liver organoids. Human cell 0 42126781
2026 Multi-omics integration reveals BPGM downregulation and potential plasma metabolite biomarkers for childhood asthma. Frontiers in pediatrics 0 42181575
2025 Single-cell metabolomics reveals that bisphosphoglycerate mutase influences oocyte maturation through glucose metabolism. Molecular human reproduction 0 40323314
2025 Metabolic reprogramming during ineffective erythropoiesis in β-thalassemia/HbE disease. Experimental and molecular pathology 0 40602081
2025 Genome-Wide Association Study and RNA-Seq Analysis Uncover Candidate Genes Controlling Growth Traits in Red Tilapia (Oreochromis spp.) Under Hyperosmotic Stress. International journal of molecular sciences 0 40650265
2025 Transcriptome and Metabolome Analyses Reveal Molecular Mechanisms Regulating Growth Traits in Large Yellow Croaker (Larimichthys crocea). International journal of molecular sciences 0 41096740
2022 Screening of activators of 2,3-diphosphoglycerate mutase from traditional Chinese herb medicines. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 0 37202106
1987 Molecular cloning of the human 2,3-bisphosphoglycerate mutase cDNA and revised amino acid sequence. Biomedica biochimica acta 0 3036106
1987 Glycerated hemoglobin alpha 2 beta 2(82) (EF6) N-epsilon-glyceryllysine: a new post-translational modification occurring in erythrocyte bisphosphoglyceromutase deficiency. Biomedica biochimica acta 0 3036109

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