Affinage

ALDOB

Fructose-bisphosphate aldolase B · UniProt P05062

Audit flag: ungrounded claim
Length
364 aa
Mass
39.5 kDa
Annotated
2026-06-09
24 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALDOB is a fructose-1,6-bisphosphate aldolase whose catalytic handling of fructose metabolites and whose moonlighting protein-scaffold functions converge on a role as a metabolic gatekeeper and tumor suppressor (PMID:33275593, PMID:20848650). Enzymatically it cleaves fructose-1-phosphate, an activity that depends on residues including R46 and Y343 (PMID:20848650); loss of this metabolic control allows F1P accumulation that drives hepatic de novo lipogenesis through GKRP and ChREBP (PMID:38372975), and in vascular smooth muscle cells fructose-driven ChREBP activation with FoxO1/3α inactivation upregulates ALDOB to increase methylglyoxal output and proliferation (PMID:28007970). Beyond catalysis, ALDOB acts as a scaffold that recruits PP2A to dephosphorylate and inactivate Akt independent of enzymatic activity, an interaction abolished by the R304A mutant and suppressing tumor growth (PMID:33275593, PMID:39899681). ALDOB also translocates to the nucleus, where it binds KAT2A to limit H3K9 acetylation at the TGFB1 promoter, repressing TGF-β and restraining Treg-mediated suppression of CD8+ T cells (PMID:38051951). Across hepatocellular, pancreatic, and gastric cancers, low ALDOB raises glycolytic flux, G6PD-driven pentose phosphate activity, and proliferation, identifying it as a suppressor of glycolytic malignancy (PMID:37597521, PMID:39302619, PMID:36749124). ALDOB expression is set epigenetically by SUV39H1-deposited H3K9me3 and transcriptionally by HNF4A, FOXP3, and FOXA2 (PMID:39302619, PMID:39899681, PMID:40778958, PMID:41513047). Under hypoxia, ALDOB is lactylated at K87 (erased by SIRT1), which recruits DRP1 via SENP3-mediated deSUMOylation to promote mitochondrial fission and smooth muscle proliferation in pulmonary hypertension (PMID:41896623).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    Established which residues are required for ALDOB catalytic activity, defining the enzymatic basis later contrasted against non-catalytic moonlighting roles.

    Evidence Recombinant ALDOB variants assayed for F1P-cleaving activity in vitro

    PMID:20848650

    Open questions at the time
    • Does not address substrate handling of fructose-1,6-bisphosphate
    • No structural model of the active site provided
    • No in vivo phenotype linked to these specific variants
  2. 2014 Medium

    First evidence that ALDOB engages a viral partner and influences survival signaling, hinting at non-metabolic protein-interaction functions.

    Evidence Yeast 2-hybrid and Co-IP of ALDOB with HBsAg, apoptosis pathway western blots in HepG2 cells

    PMID:25072145

    Open questions at the time
    • Mechanism by which the complex modulates Akt/GSK-3β phosphorylation unresolved
    • Direct vs indirect effect on Bcl-2 family proteins not separated
    • Single cell line
  3. 2016 Medium

    Showed that fructose-responsive transcription factors set ALDOB levels to control downstream methylglyoxal production, linking ALDOB to vascular remodeling.

    Evidence siRNA knockdown of ChREBP/FoxO, Akt1 inhibition, nuclear fractionation, fructose-fed mouse model

    PMID:28007970

    Open questions at the time
    • Direct promoter occupancy of ChREBP at ALDOB not fully resolved
    • Contribution of ALDOB enzymatic activity to MG production not isolated
    • Single lab
  4. 2020 High

    Defined ALDOB's catalysis-independent scaffolding role: it recruits PP2A to dephosphorylate p-Akt, establishing a tumor-suppressive non-enzymatic mechanism.

    Evidence Reciprocal Co-IP, R304A interaction-disrupting mutant, xenograft models, viability/glucose-uptake assays

    PMID:33275593

    Open questions at the time
    • Structural basis of the ALDOB-Akt-PP2A scaffold unknown
    • Determinants of complex assembly beyond R304 unmapped
    • Tissue specificity of the scaffold not defined
  5. 2023 High

    Revealed a nuclear, chromatin-directed function for ALDOB, connecting it to immune evasion through KAT2A and TGFB1 repression.

    Evidence Co-IP, ChIP at TGFB1 promoter, nuclear fractionation, ALDOB knockout mouse tumor models, antibody blockade

    PMID:38051951

    Open questions at the time
    • Signal triggering nuclear translocation of ALDOB unknown
    • Whether KAT2A inhibition is direct enzymatic interference unresolved
    • Genome-wide chromatin targets beyond TGFB1 not mapped
  6. 2023 Medium

    Demonstrated that low ALDOB reprograms glycolysis and the pentose phosphate pathway to confer chemoresistance, generalizing its tumor-suppressive metabolic role across cancers.

    Evidence PDAC organoid metabolomics, ALDOB gain-of-function rescue, GLUT1 inhibition, G6PD assays; parallel HCC siRNA/overexpression with glycolytic and invasion assays

    PMID:36749124 PMID:37597521

    Open questions at the time
    • Whether metabolic effects require ALDOB catalysis vs scaffold function not separated
    • Mechanism linking ALDOB loss to G6PD elevation incomplete
    • Single-lab organoid systems
  7. 2024 Medium

    Identified epigenetic and post-translational layers controlling ALDOB: SUV39H1-mediated H3K9me3 silencing, DUSP4-mediated dephosphorylation, and F1P-driven lipogenesis in its absence.

    Evidence ChIP for H3K9me3 at ALDOB promoter with rescue; IP-MS of DUSP4-ALDOB with G6PD readout; Aldob-/-;Gckr-/- mice with ChREBP knockdown and isotope tracing

    PMID:38372975 PMID:38843658 PMID:39302619

    Open questions at the time
    • Site of ALDOB phosphorylation targeted by DUSP4 not defined
    • GKRP/ChREBP interventions did not reduce intrahepatic triglyceride, leaving lipid phenotype partly unexplained
    • Cross-tissue generality of SUV39H1 silencing untested
  8. 2025 Medium

    Mapped the upstream transcriptional network activating ALDOB (HNF4A, FOXP3, FOXA2) and tied it to suppression of glycolysis, drug response, and Akt inhibition.

    Evidence ChIP and dual-luciferase promoter assays for HNF4A/FOXP3/FOXA2; Co-IP of ALDOB-AKT1; MeRIP/RIP for m6A control of FOXP3; rescue and xenograft models

    PMID:39899681 PMID:40778958 PMID:41513047

    Open questions at the time
    • Relative contribution of each transcription factor in a given tissue unresolved
    • Whether these regulators act combinatorially not tested
    • FOXA2-driven β-oxidation link to ALDOB enzymatic function not isolated
  9. 2026 Medium

    Discovered hypoxia-induced K87 lactylation as a modification that couples ALDOB to mitochondrial fission machinery, expanding its role into pulmonary hypertension.

    Evidence Lactylomic profiling, lactylation-mimetic/-deficient mutants, DRP1 Co-IP, SENP3 assays, SIRT1 delactylase identification, rodent PH models

    PMID:41896623

    Open questions at the time
    • How K87 lactylation mechanistically promotes DRP1 recruitment unresolved
    • Whether this PTM affects the Akt/PP2A scaffold function unknown
    • Single-lab disease model

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ALDOB's enzymatic activity, cytoplasmic scaffolding of Akt/PP2A, and nuclear chromatin functions are coordinately controlled within a single cell and which is dominant in defined tissue contexts.
  • No structural model integrating catalytic and scaffold conformations
  • Signals partitioning ALDOB between cytoplasm, nucleus, and mitochondria undefined
  • Catalysis-dependent vs -independent contributions to tumor suppression not cleanly separated across cancers

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 1 GO:0016829 lyase activity 1 GO:0060090 molecular adaptor activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 2
Partners
AKT1DRP1DUSP4HBSAGKAT2APP2A

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 ALDOB forms a protein complex with Akt and protein phosphatase 2A (PP2A), acting as a scaffold that recruits PP2A to dephosphorylate phosphorylated Akt (p-Akt), thereby suppressing Akt activity and tumor growth; this scaffolding function is independent of ALDOB's enzymatic activity, as demonstrated by the R304A mutant (which disrupts Aldob/Akt interaction) restoring Akt activity. Co-immunoprecipitation, mutagenesis (R304A), xenograft mouse models, loss-of-function experiments, cell viability/cycle/glucose uptake assays PLoS biology High 33275593
2023 ALDOB translocates to the nucleus and interacts with lysine acetyltransferase 2A (KAT2A), leading to inhibition of H3K9 acetylation at the TGFB1 promoter and thereby suppressing TGFB1 transcription; loss of ALDOB in tumor cells upregulates TGF-β, increases Treg cells, and impairs CD8+ T cell activity. Co-immunoprecipitation, ChIP assay, nuclear fractionation/localization experiments, ALDOB knockout/knockdown mouse models, subcutaneous tumor models, combinatorial antibody blockade experiments Hepatology (Baltimore, Md.) High 38051951
2023 In pancreatic cancer, low ALDOB expression combined with high GLUT1 leads to increased glycolytic flux and elevated G6PD activity driving pentose phosphate pathway and pyrimidine biosynthesis; increasing ALDOB expression reverses these metabolic phenotypes and chemotherapy resistance. PDAC organoid metabolomics, ALDOB gain-of-function experiments, GLUT1 inhibition, G6PD activity assays, glucose metabolism flux measurements Cell reports. Medicine Medium 37597521
2014 ALDOB binds directly to hepatitis B surface antigen (HBsAg S region); co-existence of HBsAg and ALDOB in the cytoplasm enhances AKT and GSK-3β phosphorylation, decreases pro-apoptotic proteins (Bax, Bid, Bim, Puma), and increases pro-survival proteins (Bcl-2, Bcl-xl, Mcl-1), inhibiting cisplatin-induced apoptosis in HepG2 cells. Yeast 2-hybrid, Co-immunoprecipitation (endogenous and exogenous), co-localization by immunofluorescence, western blot for apoptosis pathway proteins Critical reviews in eukaryotic gene expression Medium 25072145
2016 Fructose activates ChREBP (by inducing cytosol-to-nucleus translocation) and inactivates FoxO1/3α (by promoting nucleus-to-cytosol shuttling via Akt1-mediated phosphorylation) to up-regulate ALDOB expression in vascular smooth muscle cells; ALDOB knockdown prevents fructose-induced methylglyoxal (MG) overproduction and VSMC proliferation. Western blotting, real-time PCR, ChREBP/FoxO1/3α knockdown (siRNA), Akt1 inhibitor, nuclear/cytosolic fractionation, ChREBP promoter binding assay, fructose-fed mouse model Clinical science (London, England : 1979) Medium 28007970
2024 DUSP4 interacts with ALDOB and inhibits G6PD activity via ALDOB dephosphorylation, thereby elevating ROS levels and enhancing therapeutic sensitivity in HER2-positive breast cancer. Immunoprecipitation and mass spectrometry (IP-MS), RT-qPCR, IC50 assays, DUSP4 knockout cells Translational oncology Medium 38843658
2024 SUV39H1 negatively regulates ALDOB expression by depositing H3K9me3 at the ALDOB promoter region; SUV39H1 knockdown reduces H3K9me3 modification at the ALDOB promoter, increases ALDOB expression, and inhibits gastric cancer cell proliferation, migration, and invasion. ChIP assay, RT-qPCR, western blot, siRNA knockdown, enzymatic inhibitors (chaetocin, F5446), xenograft experiment Cell biochemistry and biophysics Medium 39302619
2024 In aldolase B deficient (Aldob-/-) mice, fructose 1-phosphate (F1P) accumulation stimulates hepatic de novo lipogenesis (DNL) via two mediators: glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP); ChREBP knockdown normalized mRNA expression of DNL enzymes and reduced fractional DNL, while Gckr knockout reduced de novo palmitate synthesis, but neither intervention reduced intrahepatic triglyceride levels. Aldob-/- mouse model crossed with Gckr-/- mice, shRNA against ChREBP, stable isotope tracing for DNL, hepatic mRNA expression analysis Molecular metabolism Medium 38372975
2025 FDFT1 downregulation decreases cholesterol and bile acid levels, which increases HNF4A transcriptional activity; HNF4A binds the ALDOB promoter to promote ALDOB transcription; ALDOB then binds AKT1 and inhibits AKT1 phosphorylation, delaying hepatocellular carcinoma progression. ChIP assay (HNF4A binding to ALDOB promoter), co-immunoprecipitation (ALDOB-AKT1), FDFT1 knockdown/overexpression, AKT inhibitor combination experiments, in vitro and in vivo models Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 39899681
2025 FOXP3 acts as a transcription factor that directly binds the ALDOB promoter and activates ALDOB transcription; this regulation is upstream-controlled by METTL14-mediated m6A modification of FOXP3 mRNA (via IGF2BP1-dependent stabilization), linking RNA methylation to ALDOB expression and suppression of HCC glycolysis. Dual luciferase reporter assay, ChIP assay (FOXP3 binding to ALDOB promoter), MeRIP assay (m6A on FOXP3), RIP assay (METTL14/IGF2BP1 interaction with FOXP3), xenograft mouse models Journal of molecular histology Medium 40778958
2026 ALDOB is lactylated at lysine 87 (K87) under hypoxic conditions; K87 lactylation amplifies glycolytic flux and recruits DRP1 to mitochondria via SENP3-mediated deSUMOylation of DRP1, facilitating mitochondrial fragmentation and driving pulmonary artery smooth muscle cell proliferation, migration, and phenotypic switching in pulmonary hypertension; SIRT1 acts as the delactylase for ALDOB-K87. Lactylomic profiling, ALDOB lactylation-mimetic and -deficient mutants, DRP1 co-immunoprecipitation, SENP3 functional assays, rodent PH models, genetic/pharmacological suppression of ALDOB lactylation in vivo Communications biology Medium 41896623
2025 ALDOB overexpression in colorectal cancer enhances WNT signaling pathway-related proteins (β-catenin and c-myc), which promotes PDL1 expression in CRC cells, thereby inhibiting CD8+ T cell proliferation and killing activity in co-culture systems. ALDOB overexpression, western blot for β-catenin/c-myc/PDL1, co-culture assays with CD8+ T cells, flow cytometry Immunology and cell biology Low 39909069
2023 ALDOB inhibition in hepatocellular carcinoma promotes upregulation of Ki67 and significantly enhances glycolytic activity, as well as proliferation, invasion, and migration of HCC cells; these effects are further amplified under hypoxic conditions, establishing ALDOB as a suppressor of glycolytic-driven malignant HCC behavior. ALDOB siRNA knockdown and overexpression in hepatoma cell lines, glycolytic activity assays, proliferation/invasion/migration assays under normoxia and hypoxia, in vivo animal tumor models Clinical science (London, England : 1979) Medium 36749124
2026 FOXA2 transcriptionally activates ALDOB expression by binding the ALDOB promoter, enhancing fatty acid β-oxidation and suppressing irinotecan sensitivity in colorectal cancer; ALDOB overexpression restores drug resistance in FOXA2-inhibited cells. Dual-luciferase reporter assay, ChIP assay (FOXA2 binding to ALDOB promoter), FOXA2 knockdown/overexpression, ALDOB overexpression rescue, fatty acid β-oxidation rate assays, xenograft tumor model Biochimica et biophysica acta. Molecular cell research Medium 41513047
2010 Recombinant ALDOB variants p.R46W and p.Y343H show particularly impaired residual catalytic activity toward fructose-1-phosphate (F1P), establishing these residues as functionally important for enzymatic activity in aldolase B. Recombinant protein expression, enzymatic activity assay toward F1P Human mutation Medium 20848650

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer. Cell reports. Medicine 73 37597521
2020 Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex. PLoS biology 55 33275593
2005 The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Human mutation 42 15880727
2023 ALDOB/KAT2A interactions epigenetically modulate TGF-β expression and T cell functions in hepatocellular carcinogenesis. Hepatology (Baltimore, Md.) 34 38051951
2025 Targeting FDFT1 Reduces Cholesterol and Bile Acid Production and Delays Hepatocellular Carcinoma Progression Through the HNF4A/ALDOB/AKT1 Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20 39899681
2010 Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion. Human mutation 20 20848650
2016 Dual effects of fructose on ChREBP and FoxO1/3α are responsible for AldoB up-regulation and vascular remodelling. Clinical science (London, England : 1979) 15 28007970
2023 ALDOB plays a tumor-suppressive role by inhibiting AKT activation in gastric cancer. Journal of Cancer 13 37576390
2023 Down-regulation of ALDOB during metabolic reprogramming mediates malignant behavior in hepatocellular carcinoma and insensitivity to postoperative adjuvant transarterial chemoembolization. Clinical science (London, England : 1979) 9 36749124
1995 Sheep gene mapping: assignment of ALDOB, CYP19, WT and SOX2 by somatic cell hybrid analysis. Animal genetics 8 7486251
2024 MRTO4 Enhances Glycolysis to Facilitate HCC Progression by Inhibiting ALDOB. Medical science monitor : international medical journal of experimental and clinical research 7 38778508
2012 A Novel Frameshift Mutation of the ALDOB Gene in a Korean Girl Presenting with Recurrent Hepatitis Diagnosed as Hereditary Fructose Intolerance. Gut and liver 7 22375183
2014 ALDOB acts as a novel HBsAg-binding protein and its coexistence inhibits cisplatin-induced HepG2 cell apoptosis. Critical reviews in eukaryotic gene expression 6 25072145
2025 ALDOB suppresses the activity of CD8+ T cells in colorectal cancer via the WNT signaling pathway. Immunology and cell biology 4 39909069
2024 DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB. Translational oncology 4 38843658
2024 Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency. Molecular metabolism 4 38972375
2026 ALDOB K87 lactylation drives mitochondrial fission and metabolic reprogramming in pulmonary hypertension. Communications biology 1 41896623
2025 Mechanism of METTL14 regulates HBV-HCC malignant progression by mediating m6A modification of FOXP3 and thus transcriptional activation of ALDOB. Journal of molecular histology 1 40778958
2024 Multi-omics analysis of a case of congenital microtia reveals aldob and oxidative stress associated with microtia etiology. Orphanet journal of rare diseases 1 38802922
2024 Characterization of a human induced pluripotent stem cell line (FDCHi015-A) derived from PBMCs of a patient harbouring ALDOB mutation. Stem cell research 1 38820866
2024 SUV39H1 Regulates Gastric Cancer Progression via the H3K9me3/ALDOB Axis. Cell biochemistry and biophysics 1 39302619
2023 Identification of a novel mutation in the ALDOB gene in hereditary fructose intolerance. Journal of pediatric endocrinology & metabolism : JPEM 1 36659819
2023 Associations between ALDOB polymorphisms and intrahepatic cholestasis of pregnancy susceptibility in the Chinese Han population. Ginekologia polska 1 37743645
2026 FOXA2/ALDOB axis modulation of fatty acid beta-oxidation influences irinotecan resistance in colorectal cancer. Biochimica et biophysica acta. Molecular cell research 0 41513047

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