{"gene":"PDHB","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2014,"finding":"Prolyl-hydroxylase PHD3 physically interacts with PDH-E1β (PDHB) and is required for maintaining PDH complex (PDC) stability and cellular PDH activity. PHD3 depletion destabilized the PDC without affecting expression or phosphorylation of PDH subunits, resulting in reduced functional PDC and resistance to cell death under prolonged hypoxia.","method":"Proteomics-based identification of PHD3-interacting proteins, Co-IP, PHD3 knockdown/knockout (PHD3-/- MEFs and MCF7 cells) with PDH activity assay, Western blot for subunit expression and E1α phosphorylation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified by proteomics and Co-IP, functional consequence confirmed by KO/KD with PDH activity assay in two cell systems; single lab","pmids":["25088999"],"is_preprint":false},{"year":2018,"finding":"PDH-E1β (PDHB) subunit levels are reduced under prolonged hypoxia and remain low after restoration of normoxia, thereby durably downregulating PDH complex activity and sustaining glycolytic activation (Warburg-like state). Silencing PDHB inhibited tumor growth despite activating glycolysis; conversely, enforced PDHB expression promoted PDH activity and malignant breast cancer growth in vivo.","method":"PDHB siRNA knockdown and stable overexpression in cancer cells; PDH activity assays; xenograft tumor growth assays; metabolic profiling","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined metabolic and in vivo phenotype, multiple orthogonal methods; single lab","pmids":["29436427"],"is_preprint":false},{"year":2004,"finding":"Missense mutations in the PDHB gene (encoding the E1β subunit) reduce immunoreactive E1β protein and cause PDH complex deficiency; PDC activity was restored in patient fibroblasts by transfection with wild-type PDHB coding sequence, establishing PDHB loss-of-function as a direct cause of PDH deficiency.","method":"Mutation identification by sequencing, immunoblot for E1β protein, complementation by transfection of wild-type PDHB in patient fibroblasts with PDH activity assay","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional complementation directly restores enzyme activity, replicated in multiple patients across multiple subsequent studies","pmids":["15138885"],"is_preprint":false},{"year":2008,"finding":"Multiple missense mutations in PDHB (R36C, C306R, D319V, I142M, W165S, Y132C) cause PDH complex deficiency with markedly reduced E1β immunoreactivity. Structural modeling indicated these mutations disrupt inter-subunit contacts and K+ ion coordination essential for E1β stability and α2β2 tetramer assembly. PDH activity in lymphocytes of heterozygous carriers was normal, consistent with recessive inheritance.","method":"PDHB sequencing in PDC-deficient patients, PDC activity assay (lymphocytes and fibroblasts), immunoblot for E1β, computer structural modeling of mutation effects","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clinical mutation series with enzyme assays and immunoblot, structural modelling; single lab, no in vitro reconstitution","pmids":["18164639"],"is_preprint":false},{"year":2001,"finding":"The 2.0 Å crystal structure of archaeal E1β (Pyrobaculum aerophilum) revealed that in the absence of its E1α partner, E1β undergoes significant structural rearrangements including rearrangement of helix C, and forms β4 tetramers in solution stabilized by a GPhiXXG helix-helix packing motif. The same GPhiXXG motif mediates the E1α–E1β interface in the human and P. putida α2β2 heterotetramers.","method":"X-ray crystallography (2.0 Å), static light scattering, sedimentation velocity analytical ultracentrifugation, comparative structural analysis with human and P. putida E1β","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with solution biophysical validation; multiple orthogonal methods in one study","pmids":["11724561"],"is_preprint":false},{"year":2001,"finding":"In maple syrup urine disease (MSUD), the S289L-β mutation in the E1β subunit of branched-chain α-ketoacid dehydrogenase (BCKDHB, related E1β) disrupts hydrogen-bonding interactions required for α2β2 heterotetramer assembly, yielding a stable but inactive αβ heterodimer. The R133P-β mutation abrogates K+ ion coordination in E1β, reducing subunit stability rather than assembly per se.","method":"Recombinant mutant E1 expression in E. coli, enzyme activity assay, thermal inactivation and free energy denaturation measurements, structure-guided analysis using human E1 crystal structure","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and stability assays; this is BCKDHB (E1β of BCKDH), not PDHB; included because it is a related E1β subunit study — NOTE: BCKDHB is a distinct gene; this paper concerns BCKDHB, not PDHB","pmids":["11448970"],"is_preprint":false},{"year":2009,"finding":"Novel homozygous (M101T) and compound heterozygous (M101V/R105Q) PDHB mutations cause PDH complex deficiency presenting as Leigh syndrome; all three mutations reduce both E1α and E1β protein levels on immunoblot, indicating that E1β instability destabilizes the entire E1 heterodimer.","method":"PDHB sequencing, PDHc and E1 activity assay in fibroblasts and muscle, immunoblot for E1α and E1β","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple patients, enzyme activity and protein stability data; single lab, no complementation","pmids":["19924563"],"is_preprint":false},{"year":2025,"finding":"The PDHB missense mutation c.575G>T (p.Arg192Leu) reduces PDHB protein stability and markedly decreases PDH enzymatic activity in transfected 293T cells, establishing pathogenicity in vitro.","method":"Whole exome sequencing, recombinant eukaryotic expression of wild-type and mutant PDHB in 293T cells, Western blot for protein stability, PDH activity assay","journal":"Italian journal of pediatrics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro functional assay with mutagenesis construct; single lab, single patient mutation","pmids":["40050878"],"is_preprint":false},{"year":2017,"finding":"miR-146b-5p directly targets the 3'-UTR of PDHB, reducing PDHB expression; overexpression of PDHB abolished the oncogenic effects of miR-146b-5p on cell growth, invasion, and glycolysis in colorectal cancer cells.","method":"miRNA overexpression/knockdown in CRC cells, 3'-UTR luciferase reporter assay, PDHB rescue overexpression, cell growth and invasion assays, glycolysis measurement, xenograft in vivo","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct targeting, rescue experiment confirms functional specificity; single lab","pmids":["28560062"],"is_preprint":false},{"year":2018,"finding":"Neuron-specific knockdown of Drosophila PDHB (dPDHB/CG11876) reduces lifespan, impairs larval and adult locomotion, causes abnormal motor neuron terminal morphology at neuromuscular junctions, mitochondrial fragmentation in brains, and aberrant photoreceptor axon targeting.","method":"Tissue-specific RNAi knockdown in Drosophila neurons (pan-neuronal Gal4 driver), lifespan assay, locomotor assay, confocal imaging of NMJs and mitochondria, eye morphology and photoreceptor axon targeting analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean neuronal KD with multiple orthogonal phenotypic readouts in vivo; single lab, Drosophila model","pmids":["29501567"],"is_preprint":false},{"year":2025,"finding":"PDHB overexpression in hepatocellular carcinoma (HCC) cells drives glycolytic reprogramming by binding to the promoter regions of SLC2A1, GPI, and PKM2 to promote glycolysis-related gene transcription, and contributes to sorafenib resistance; isoacteoside was identified as a targeted inhibitor of PDHB with antitumor effects.","method":"PDHB overexpression in HCC cells in vitro and xenograft in vivo, ChIP/promoter-binding assay for SLC2A1/GPI/PKM2, metabolic assays, drug resistance assay, in vivo combination treatment","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies promoter binding, in vivo validation; single lab, mechanistic details from abstract are limited","pmids":["39922943"],"is_preprint":false},{"year":2025,"finding":"OGDHL (α-ketoglutarate dehydrogenase complex subunit) physically interacts with PDHB in gastric cancer cells; disruption of this interaction via miR-1343-3p-mediated OGDHL downregulation destabilizes PDHB, reduces pyruvate oxidative decarboxylation, and decreases acetyl-CoA and ATP production, inhibiting cancer cell proliferation.","method":"Co-immunoprecipitation (Co-IP) confirming OGDHL–PDHB interaction, RIP for miRNA–mRNA interaction, Western blot for PDHB protein stability, ELISA and ATP detection, siRNA knockdown, xenograft in vivo","journal":"Discover oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishes protein interaction, functional metabolic readouts in vitro and in vivo; single lab","pmids":["41420718"],"is_preprint":false},{"year":1983,"finding":"PDH phosphate (PDHb) phosphatase in rat brain copurifies with mitochondrial marker enzymes and is located in mitochondria; the enzyme shows saturable kinetics, requires Mg2+ and Ca2+, is inhibited by NaF and K-phosphate, and functions to dephosphorylate and activate phosphorylated (inactive) PDH complex.","method":"Subcellular fractionation of rat brain, PDHb phosphatase activity assay using purified phospho-PDH complex as substrate, kinetic analysis, inhibitor studies","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzyme activity and subcellular localization by fractionation with marker enzymes; single lab, in vitro biochemistry","pmids":["6300332"],"is_preprint":false},{"year":2026,"finding":"TGFβ signaling upregulates PDHB during definitive endoderm differentiation from human pluripotent stem cells, driving a metabolic switch with enhanced TCA cycle activity and oxidative phosphorylation. Mechanistically, PDHB-mediated pyruvate entry into the TCA cycle sustains intracellular ATP levels required for the activity of the BRG1-centered BAF chromatin remodeling complex, thereby promoting chromatin accessibility and endodermal gene programs.","method":"PDHB disruption during hPSC endoderm differentiation, metabolic assays (lactate, TCA metabolites, OXPHOS), ATP measurement, BRG1/BAF complex activity assay, chromatin accessibility (ATAC-seq or equivalent), endoderm marker expression","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional and metabolic assays linking PDHB to chromatin remodeling via ATP; single lab, abstract-level detail","pmids":["41702907"],"is_preprint":false}],"current_model":"PDHB (PDH E1β) is an essential structural and catalytic subunit of the pyruvate dehydrogenase complex (PDC) that forms an α2β2 heterotetramer with E1α; loss-of-function mutations in PDHB destabilize E1β and the entire PDC, abolishing conversion of pyruvate to acetyl-CoA and causing primary lactic acidosis; PDC activity is regulated by PHD3-mediated complex stabilization and by reversible phosphorylation/dephosphorylation of E1α catalyzed by PDH kinases and the mitochondria-localized PDHb phosphatase; PDHB levels are durably reduced under prolonged hypoxia to sustain the Warburg-like glycolytic state in cancer cells; additionally, PDHB interacts with OGDHL and, in some contexts, binds glycolytic gene promoters to regulate metabolic reprogramming, and its TGFβ-driven upregulation during endoderm differentiation supplies ATP for BRG1-dependent chromatin remodeling."},"narrative":{"mechanistic_narrative":"PDHB encodes the E1β subunit of the mitochondrial pyruvate dehydrogenase complex (PDC), which assembles with E1α into an α2β2 heterotetramer to catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA, the committed entry of glycolytic carbon into the TCA cycle [PMID:11724561, PMID:19924563]. Recessive loss-of-function missense mutations in PDHB reduce E1β immunoreactivity and abolish PDC activity, causing primary PDH complex deficiency that can present as Leigh syndrome; complementation with wild-type PDHB restores enzyme activity in patient fibroblasts, and structural and stability analyses show that pathogenic substitutions disrupt inter-subunit contacts and K+ ion coordination required for tetramer assembly, with E1β destabilization in turn destabilizing E1α [PMID:15138885, PMID:18164639, PMID:19924563, PMID:40050878]. The complex is stabilized post-translationally through physical interaction of PDHB with the prolyl-hydroxylase PHD3, which is required to maintain functional PDC and cellular PDH activity [PMID:25088999], while a mitochondrial PDH phosphatase reactivates the phosphorylated, inactive complex [PMID:6300332]. Beyond its canonical catalytic role, PDHB is a node in metabolic reprogramming: its levels are durably reduced under prolonged hypoxia to sustain a glycolytic Warburg-like state, and PDHB is itself regulated by miR-146b-5p and stabilized through interaction with OGDHL, with manipulation of PDHB altering glycolysis, acetyl-CoA/ATP output, and tumor growth in breast, colorectal, gastric, and hepatocellular cancers [PMID:29436427, PMID:28560062, PMID:39922943, PMID:41420718]. In hepatocellular carcinoma PDHB binds the promoters of glycolytic genes (SLC2A1, GPI, PKM2) to drive their transcription [PMID:39922943], and during TGFβ-driven endoderm differentiation PDHB-supplied ATP supports BRG1/BAF chromatin remodeling and endodermal gene programs [PMID:41702907]. Neuronal knockdown of Drosophila PDHB impairs lifespan, locomotion, neuromuscular junction morphology, and mitochondrial integrity, underscoring its requirement for neuronal energy metabolism [PMID:29501567].","teleology":[{"year":2001,"claim":"The structural basis for how E1β assembles and what stabilizes the catalytic core was unknown; the archaeal E1β crystal structure defined the GPhiXXG helix-helix motif mediating the E1α–E1β interface and showed E1β rearranges and self-associates in the absence of E1α.","evidence":"X-ray crystallography of archaeal E1β with light scattering and analytical ultracentrifugation, compared to human and P. putida heterotetramers","pmids":["11724561"],"confidence":"High","gaps":["Structure is of an archaeal ortholog, not human PDHB","Does not address regulation of assembly in cells","Catalytic mechanism within the assembled tetramer not resolved"]},{"year":2004,"claim":"Whether PDHB mutations directly cause PDH deficiency rather than being incidental variants was unresolved; complementation of patient fibroblasts with wild-type PDHB restored PDC activity, establishing PDHB loss-of-function as a direct genetic cause.","evidence":"Mutation sequencing, immunoblot for E1β, and functional complementation by wild-type PDHB transfection in patient fibroblasts","pmids":["15138885"],"confidence":"High","gaps":["Per-mutation structural mechanism not defined","Does not address tissue-specific phenotype variability"]},{"year":2008,"claim":"How specific PDHB point mutations cause deficiency was unclear; a mutation series with structural modeling showed pathogenic substitutions disrupt inter-subunit contacts and K+ coordination needed for E1β stability and α2β2 assembly, and confirmed recessive inheritance.","evidence":"PDHB sequencing, PDC activity assays in lymphocytes and fibroblasts, immunoblot, and computational structural modeling","pmids":["18164639"],"confidence":"Medium","gaps":["No in vitro reconstitution of mutant assembly","Modeling not validated by experimental structures of mutants"]},{"year":2009,"claim":"Whether E1β instability affects the partner subunit was unknown; PDHB mutations causing Leigh syndrome reduced both E1α and E1β protein levels, demonstrating that E1β destabilization collapses the entire E1 heterodimer.","evidence":"PDHB sequencing, PDHc/E1 activity assays in fibroblasts and muscle, immunoblot for E1α and E1β","pmids":["19924563"],"confidence":"Medium","gaps":["No complementation performed","Mechanism of co-degradation not defined"]},{"year":2025,"claim":"Continued discovery of pathogenic alleles; the c.575G>T (p.Arg192Leu) variant was shown to reduce PDHB stability and PDH activity in cells, confirming pathogenicity.","evidence":"Whole exome sequencing plus recombinant expression of wild-type and mutant PDHB in 293T cells with Western blot and PDH activity assay","pmids":["40050878"],"confidence":"Medium","gaps":["Single patient, single mutation","Stability mechanism not structurally resolved"]},{"year":1983,"claim":"The enzyme reactivating the phosphorylated PDC and its location were unresolved; PDHb phosphatase was localized to mitochondria and shown to dephosphorylate and activate inactive phospho-PDH in a Mg2+/Ca2+-dependent manner.","evidence":"Subcellular fractionation of rat brain with marker enzymes, phosphatase activity assay on purified phospho-PDH substrate, kinetic and inhibitor studies","pmids":["6300332"],"confidence":"Medium","gaps":["Performed in rat brain, not human","Does not address regulation by upstream signals","PDHB subunit-specific contribution to phosphatase substrate not isolated"]},{"year":2014,"claim":"How PDC stability is maintained beyond intrinsic assembly was unknown; PHD3 was identified as a physical PDHB interactor required to maintain PDC stability and activity, independent of subunit expression or phosphorylation, linking complex stability to hypoxic cell-death resistance.","evidence":"Proteomic interactor identification, Co-IP, PHD3 knockdown/knockout in MEFs and MCF7 cells with PDH activity assays and immunoblots","pmids":["25088999"],"confidence":"Medium","gaps":["Hydroxylation site/mechanism on PDC not defined","Single lab","Direct vs indirect stabilization not fully resolved"]},{"year":2018,"claim":"Whether PDHB levels actively shape the cancer glycolytic state was unknown; prolonged hypoxia durably reduced PDHB to sustain a Warburg-like state, and PDHB manipulation bidirectionally altered PDH activity and tumor growth in vivo.","evidence":"siRNA knockdown and stable overexpression in cancer cells, PDH activity assays, xenograft growth assays, metabolic profiling","pmids":["29436427"],"confidence":"Medium","gaps":["Mechanism of durable suppression not defined","Single lab"]},{"year":2017,"claim":"How PDHB is downregulated in cancer was partly unresolved; miR-146b-5p was shown to directly target the PDHB 3'-UTR, and PDHB re-expression reversed the miRNA's oncogenic effects on growth, invasion, and glycolysis.","evidence":"miRNA gain/loss-of-function, 3'-UTR luciferase reporter, PDHB rescue, growth/invasion/glycolysis assays, xenograft in colorectal cancer","pmids":["28560062"],"confidence":"Medium","gaps":["Single lab","Other regulatory inputs not surveyed"]},{"year":2025,"claim":"Non-canonical functions of PDHB were unknown; PDHB was found to bind glycolytic gene promoters (SLC2A1, GPI, PKM2) to drive their transcription and contribute to sorafenib resistance in HCC, with isoacteoside identified as an inhibitor.","evidence":"PDHB overexpression in HCC cells and xenografts, ChIP/promoter-binding assays, metabolic and drug-resistance assays, in vivo combination treatment","pmids":["39922943"],"confidence":"Medium","gaps":["Mechanism of nuclear/chromatin localization of a mitochondrial enzyme not defined","Direct DNA binding vs co-factor recruitment not resolved","Single lab, abstract-level mechanistic detail"]},{"year":2025,"claim":"A new PDHB stabilizing partner was identified; OGDHL physically interacts with PDHB in gastric cancer, and disrupting this interaction destabilizes PDHB, reduces pyruvate decarboxylation, and lowers acetyl-CoA/ATP, impairing proliferation.","evidence":"Co-IP for OGDHL–PDHB, RIP for miRNA–mRNA, immunoblot for PDHB stability, ELISA/ATP assays, siRNA knockdown, xenograft","pmids":["41420718"],"confidence":"Medium","gaps":["Structural basis of OGDHL–PDHB interaction unknown","Reciprocal validation limited","Single lab"]},{"year":2026,"claim":"Whether PDHB-derived energy metabolism feeds developmental chromatin programs was unknown; TGFβ-induced PDHB during endoderm differentiation supplies ATP that sustains BRG1/BAF chromatin remodeling and endodermal gene activation.","evidence":"PDHB disruption during hPSC endoderm differentiation, metabolic/OXPHOS/ATP assays, BRG1/BAF activity and chromatin accessibility assays, marker expression","pmids":["41702907"],"confidence":"Medium","gaps":["Direct vs indirect link between ATP and BAF activity not fully isolated","Single lab, abstract-level detail"]},{"year":2018,"claim":"The in vivo neuronal requirement for PDHB was tested; pan-neuronal knockdown of Drosophila PDHB shortened lifespan and impaired locomotion, NMJ morphology, mitochondrial integrity, and axon targeting, establishing its necessity for neuronal energy metabolism.","evidence":"Tissue-specific RNAi in Drosophila neurons, lifespan/locomotor assays, confocal imaging of NMJs and mitochondria, photoreceptor axon analysis","pmids":["29501567"],"confidence":"Medium","gaps":["Drosophila model; human neuronal relevance inferred","Cell-autonomous metabolic cause vs developmental defect not fully separated"]},{"year":null,"claim":"How a canonically mitochondrial E1β subunit reaches gene promoters and whether its chromatin-associated and complex-stabilizing functions are mechanistically separable from its catalytic role remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PDHB on DNA","Nuclear import/localization mechanism undefined","Interplay between PHD3, OGDHL stabilization, and catalytic activity not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[2,4,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,6]}],"complexes":["pyruvate dehydrogenase complex"],"partners":["PHD3","OGDHL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P11177","full_name":"Pyruvate dehydrogenase E1 component subunit beta, mitochondrial","aliases":[],"length_aa":359,"mass_kda":39.2,"function":"Together with PDHA1 forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex (PubMed:17474719, PubMed:19081061). The PDH complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3) (Probable). The E1 subunit catalyzes both the thiamine pyrophosphate (TPP)-dependent decarboxylation of pyruvate and the reductive acetylation of a lipoyl group covalently linked to the lipoyl-bearing domains of E2 (PubMed:19081061)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/P11177/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDHB","classification":"Not Classified","n_dependent_lines":61,"n_total_lines":1208,"dependency_fraction":0.050496688741721855},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ASS1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PHGDH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PDHB","total_profiled":1310},"omim":[{"mim_id":"616299","title":"LIPOYLTRANSFERASE 1 DEFICIENCY; LIPT1D","url":"https://www.omim.org/entry/616299"},{"mim_id":"614111","title":"PYRUVATE DEHYDROGENASE E1-BETA DEFICIENCY; PDHBD","url":"https://www.omim.org/entry/614111"},{"mim_id":"608769","title":"PYRUVATE DEHYDROGENASE COMPLEX, COMPONENT X; PDHX","url":"https://www.omim.org/entry/608769"},{"mim_id":"608708","title":"BROTHER OF CDON; BOC","url":"https://www.omim.org/entry/608708"},{"mim_id":"312170","title":"PYRUVATE DEHYDROGENASE E1-ALPHA DEFICIENCY; PDHAD","url":"https://www.omim.org/entry/312170"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"tongue","ntpm":279.4}],"url":"https://www.proteinatlas.org/search/PDHB"},"hgnc":{"alias_symbol":["PDHE1B","E1beta"],"prev_symbol":[]},"alphafold":{"accession":"P11177","domains":[{"cath_id":"3.40.50.970","chopping":"32-216","consensus_level":"high","plddt":98.5841,"start":32,"end":216},{"cath_id":"3.40.50.920","chopping":"228-356","consensus_level":"high","plddt":98.7408,"start":228,"end":356}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P11177","model_url":"https://alphafold.ebi.ac.uk/files/AF-P11177-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P11177-F1-predicted_aligned_error_v6.png","plddt_mean":94.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDHB","jax_strain_url":"https://www.jax.org/strain/search?query=PDHB"},"sequence":{"accession":"P11177","fasta_url":"https://rest.uniprot.org/uniprotkb/P11177.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P11177/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P11177"}},"corpus_meta":[{"pmid":"28560062","id":"PMC_28560062","title":"miR-146b-5p regulates cell growth, invasion, and metabolism by targeting PDHB in colorectal cancer.","date":"2017","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28560062","citation_count":81,"is_preprint":false},{"pmid":"29436427","id":"PMC_29436427","title":"Pyruvate Dehydrogenase PDH-E1β Controls Tumor Progression by Altering the Metabolic Status of Cancer Cells.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29436427","citation_count":52,"is_preprint":false},{"pmid":"15138885","id":"PMC_15138885","title":"Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency.","date":"2004","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15138885","citation_count":36,"is_preprint":false},{"pmid":"18164639","id":"PMC_18164639","title":"Mutations of the E1beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency.","date":"2008","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/18164639","citation_count":35,"is_preprint":false},{"pmid":"11976308","id":"PMC_11976308","title":"The E1beta and E2 subunits of the Bacillus subtilis pyruvate dehydrogenase complex are involved in regulation of sporulation.","date":"2002","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/11976308","citation_count":34,"is_preprint":false},{"pmid":"33118833","id":"PMC_33118833","title":"LncRNA MEG3 promotes endoplasmic reticulum stress and suppresses proliferation and invasion of colorectal carcinoma cells through the MEG3/miR-103a-3p/PDHB ceRNA pathway.","date":"2020","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/33118833","citation_count":34,"is_preprint":false},{"pmid":"6300332","id":"PMC_6300332","title":"Pyruvate dehydrogenase phosphate (PDHb) phosphatase in brain: activity, properties, and subcellular localization.","date":"1983","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6300332","citation_count":33,"is_preprint":false},{"pmid":"25088999","id":"PMC_25088999","title":"Prolyl-hydroxylase PHD3 interacts with pyruvate dehydrogenase (PDH)-E1β and regulates the cellular PDH activity.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25088999","citation_count":29,"is_preprint":false},{"pmid":"36750722","id":"PMC_36750722","title":"PDHB-AS suppresses cervical cancer progression and cisplatin resistance via inhibition on Wnt/β-catenin pathway.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36750722","citation_count":28,"is_preprint":false},{"pmid":"27379520","id":"PMC_27379520","title":"Molecular Characterization and Transcriptional Regulation Analysis of the Bovine PDHB Gene.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27379520","citation_count":22,"is_preprint":false},{"pmid":"19924563","id":"PMC_19924563","title":"PDH E1β deficiency with novel mutations in two patients with Leigh syndrome.","date":"2009","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/19924563","citation_count":20,"is_preprint":false},{"pmid":"37641032","id":"PMC_37641032","title":"Cuproptosis related gene PDHB is identified as a biomarker inversely associated with the progression of clear cell renal cell carcinoma.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37641032","citation_count":19,"is_preprint":false},{"pmid":"25799063","id":"PMC_25799063","title":"Disruption of the pdhB pyruvate dehydrogenase [corrected] gene affects colony morphology, in vitro growth and cell invasiveness of Mycoplasma agalactiae.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25799063","citation_count":18,"is_preprint":false},{"pmid":"11724561","id":"PMC_11724561","title":"3D structure and significance of the GPhiXXG helix packing motif in tetramers of the E1beta subunit of pyruvate dehydrogenase from the archeon Pyrobaculum aerophilum.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11724561","citation_count":18,"is_preprint":false},{"pmid":"29501567","id":"PMC_29501567","title":"Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29501567","citation_count":15,"is_preprint":false},{"pmid":"22593002","id":"PMC_22593002","title":"Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1α and E1β.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22593002","citation_count":14,"is_preprint":false},{"pmid":"11448970","id":"PMC_11448970","title":"Biochemical basis of type IB (E1beta ) mutations in maple syrup urine disease. A prevalent allele in patients from the Druze kindred in Israel.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11448970","citation_count":14,"is_preprint":false},{"pmid":"39922943","id":"PMC_39922943","title":"Isoacteoside alleviates hepatocellular carcinoma progression by inhibiting PDHB-mediated reprogramming of glucose metabolism.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39922943","citation_count":11,"is_preprint":false},{"pmid":"36816316","id":"PMC_36816316","title":"A combined analysis of bulk and single-cell sequencing data reveals metabolic enzyme, pyruvate dehydrogenase E1 subunit beta (PDHB), as a prediction biomarker for the tumor immune response and immunotherapy.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/36816316","citation_count":11,"is_preprint":false},{"pmid":"37350959","id":"PMC_37350959","title":"Integrated single-cell and bulk characterization of cuproptosis key regulator PDHB and association with tumor microenvironment infiltration in clear cell renal cell carcinoma.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37350959","citation_count":10,"is_preprint":false},{"pmid":"6087208","id":"PMC_6087208","title":"Pyruvate dehydrogenase phosphate (PDHb) phosphatase activity in fibroblasts from Leigh's disease.","date":"1984","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/6087208","citation_count":10,"is_preprint":false},{"pmid":"22569713","id":"PMC_22569713","title":"Intraabdominal adhesion formation is associated with differential mRNA expression of metabolic genes PDHb and SDHa.","date":"2012","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/22569713","citation_count":7,"is_preprint":false},{"pmid":"10686156","id":"PMC_10686156","title":"Staphylococcal protein A as a fusion partner directs secretion of the e1alpha and e1beta subunits of pea mitochondrial pyruvate dehydrogenase by Bacillus subtilis.","date":"2000","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/10686156","citation_count":5,"is_preprint":false},{"pmid":"17524396","id":"PMC_17524396","title":"Branched chain alpha-keto acid dehydrogenase, E1-beta subunit gene is associated with premature ovarian failure.","date":"2007","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/17524396","citation_count":5,"is_preprint":false},{"pmid":"33313332","id":"PMC_33313332","title":"A novel chimeric recombinant protein PDHB-P80 of Mycoplasma agalactiae as a potential diagnostic tool.","date":"2020","source":"Molecular biology research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33313332","citation_count":4,"is_preprint":false},{"pmid":"34078216","id":"PMC_34078216","title":"Protective effects of repetitive transcranial magnetic stimulation against 6-OHDA-induced Parkinson's symptoms in a mice model: the key role of miR-409-3p/PDHB axis.","date":"2021","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34078216","citation_count":4,"is_preprint":false},{"pmid":"40579136","id":"PMC_40579136","title":"[Salidroside inhibits proliferation of gastric cancer cells by regulating the miR-1343-3p-OGDHL/PDHB glucose metabolic axis].","date":"2025","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/40579136","citation_count":2,"is_preprint":false},{"pmid":"40050878","id":"PMC_40050878","title":"A missense mutation in PDHB gene: identification of the patient with pyruvate dehydrogenase deficiency and demonstration of pathogenicity in vitro.","date":"2025","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40050878","citation_count":1,"is_preprint":false},{"pmid":"41232890","id":"PMC_41232890","title":"Preparation of monoclonal antibodies against pyruvate dehydrogenase E1 component beta subunit (PDHB) protein of Mycoplasma bovis and the identification of its two novel B-cell epitopes.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41232890","citation_count":1,"is_preprint":false},{"pmid":"38147995","id":"PMC_38147995","title":"[Identification and expression analysis of apple PDHB-1 gene family].","date":"2023","source":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38147995","citation_count":0,"is_preprint":false},{"pmid":"41420718","id":"PMC_41420718","title":"miR-1343-3p regulating OGDHL/PDHB-pyruvate glucose metabolic reprogramming against gastric cancer cell proliferation.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41420718","citation_count":0,"is_preprint":false},{"pmid":"21469508","id":"PMC_21469508","title":"Polymorphisms in promoter regions of PDHB, SORBS1, and EDG1 genes showing marbling-associated expression changes.","date":"2007","source":"Research communications in molecular pathology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21469508","citation_count":0,"is_preprint":false},{"pmid":"41702907","id":"PMC_41702907","title":"TGFβ-activated PDHB promotes mitochondrial pyruvate metabolism and contributes to human endoderm differentiation via ATP-dependent BRG1.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41702907","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.16.682926","title":"Integrated phenotypic and proteomic screening identifies top-tier Alzheimer’s disease therapeutic targets","date":"2025-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.16.682926","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18420,"output_tokens":3878,"usd":0.056715,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11867,"output_tokens":4617,"usd":0.08738,"stage2_stop_reason":"end_turn"},"total_usd":0.144095,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Prolyl-hydroxylase PHD3 physically interacts with PDH-E1β (PDHB) and is required for maintaining PDH complex (PDC) stability and cellular PDH activity. PHD3 depletion destabilized the PDC without affecting expression or phosphorylation of PDH subunits, resulting in reduced functional PDC and resistance to cell death under prolonged hypoxia.\",\n      \"method\": \"Proteomics-based identification of PHD3-interacting proteins, Co-IP, PHD3 knockdown/knockout (PHD3-/- MEFs and MCF7 cells) with PDH activity assay, Western blot for subunit expression and E1α phosphorylation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified by proteomics and Co-IP, functional consequence confirmed by KO/KD with PDH activity assay in two cell systems; single lab\",\n      \"pmids\": [\"25088999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDH-E1β (PDHB) subunit levels are reduced under prolonged hypoxia and remain low after restoration of normoxia, thereby durably downregulating PDH complex activity and sustaining glycolytic activation (Warburg-like state). Silencing PDHB inhibited tumor growth despite activating glycolysis; conversely, enforced PDHB expression promoted PDH activity and malignant breast cancer growth in vivo.\",\n      \"method\": \"PDHB siRNA knockdown and stable overexpression in cancer cells; PDH activity assays; xenograft tumor growth assays; metabolic profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined metabolic and in vivo phenotype, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"29436427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Missense mutations in the PDHB gene (encoding the E1β subunit) reduce immunoreactive E1β protein and cause PDH complex deficiency; PDC activity was restored in patient fibroblasts by transfection with wild-type PDHB coding sequence, establishing PDHB loss-of-function as a direct cause of PDH deficiency.\",\n      \"method\": \"Mutation identification by sequencing, immunoblot for E1β protein, complementation by transfection of wild-type PDHB in patient fibroblasts with PDH activity assay\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional complementation directly restores enzyme activity, replicated in multiple patients across multiple subsequent studies\",\n      \"pmids\": [\"15138885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Multiple missense mutations in PDHB (R36C, C306R, D319V, I142M, W165S, Y132C) cause PDH complex deficiency with markedly reduced E1β immunoreactivity. Structural modeling indicated these mutations disrupt inter-subunit contacts and K+ ion coordination essential for E1β stability and α2β2 tetramer assembly. PDH activity in lymphocytes of heterozygous carriers was normal, consistent with recessive inheritance.\",\n      \"method\": \"PDHB sequencing in PDC-deficient patients, PDC activity assay (lymphocytes and fibroblasts), immunoblot for E1β, computer structural modeling of mutation effects\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clinical mutation series with enzyme assays and immunoblot, structural modelling; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"18164639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The 2.0 Å crystal structure of archaeal E1β (Pyrobaculum aerophilum) revealed that in the absence of its E1α partner, E1β undergoes significant structural rearrangements including rearrangement of helix C, and forms β4 tetramers in solution stabilized by a GPhiXXG helix-helix packing motif. The same GPhiXXG motif mediates the E1α–E1β interface in the human and P. putida α2β2 heterotetramers.\",\n      \"method\": \"X-ray crystallography (2.0 Å), static light scattering, sedimentation velocity analytical ultracentrifugation, comparative structural analysis with human and P. putida E1β\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with solution biophysical validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"11724561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In maple syrup urine disease (MSUD), the S289L-β mutation in the E1β subunit of branched-chain α-ketoacid dehydrogenase (BCKDHB, related E1β) disrupts hydrogen-bonding interactions required for α2β2 heterotetramer assembly, yielding a stable but inactive αβ heterodimer. The R133P-β mutation abrogates K+ ion coordination in E1β, reducing subunit stability rather than assembly per se.\",\n      \"method\": \"Recombinant mutant E1 expression in E. coli, enzyme activity assay, thermal inactivation and free energy denaturation measurements, structure-guided analysis using human E1 crystal structure\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and stability assays; this is BCKDHB (E1β of BCKDH), not PDHB; included because it is a related E1β subunit study — NOTE: BCKDHB is a distinct gene; this paper concerns BCKDHB, not PDHB\",\n      \"pmids\": [\"11448970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Novel homozygous (M101T) and compound heterozygous (M101V/R105Q) PDHB mutations cause PDH complex deficiency presenting as Leigh syndrome; all three mutations reduce both E1α and E1β protein levels on immunoblot, indicating that E1β instability destabilizes the entire E1 heterodimer.\",\n      \"method\": \"PDHB sequencing, PDHc and E1 activity assay in fibroblasts and muscle, immunoblot for E1α and E1β\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple patients, enzyme activity and protein stability data; single lab, no complementation\",\n      \"pmids\": [\"19924563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PDHB missense mutation c.575G>T (p.Arg192Leu) reduces PDHB protein stability and markedly decreases PDH enzymatic activity in transfected 293T cells, establishing pathogenicity in vitro.\",\n      \"method\": \"Whole exome sequencing, recombinant eukaryotic expression of wild-type and mutant PDHB in 293T cells, Western blot for protein stability, PDH activity assay\",\n      \"journal\": \"Italian journal of pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro functional assay with mutagenesis construct; single lab, single patient mutation\",\n      \"pmids\": [\"40050878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-146b-5p directly targets the 3'-UTR of PDHB, reducing PDHB expression; overexpression of PDHB abolished the oncogenic effects of miR-146b-5p on cell growth, invasion, and glycolysis in colorectal cancer cells.\",\n      \"method\": \"miRNA overexpression/knockdown in CRC cells, 3'-UTR luciferase reporter assay, PDHB rescue overexpression, cell growth and invasion assays, glycolysis measurement, xenograft in vivo\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct targeting, rescue experiment confirms functional specificity; single lab\",\n      \"pmids\": [\"28560062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Neuron-specific knockdown of Drosophila PDHB (dPDHB/CG11876) reduces lifespan, impairs larval and adult locomotion, causes abnormal motor neuron terminal morphology at neuromuscular junctions, mitochondrial fragmentation in brains, and aberrant photoreceptor axon targeting.\",\n      \"method\": \"Tissue-specific RNAi knockdown in Drosophila neurons (pan-neuronal Gal4 driver), lifespan assay, locomotor assay, confocal imaging of NMJs and mitochondria, eye morphology and photoreceptor axon targeting analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean neuronal KD with multiple orthogonal phenotypic readouts in vivo; single lab, Drosophila model\",\n      \"pmids\": [\"29501567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDHB overexpression in hepatocellular carcinoma (HCC) cells drives glycolytic reprogramming by binding to the promoter regions of SLC2A1, GPI, and PKM2 to promote glycolysis-related gene transcription, and contributes to sorafenib resistance; isoacteoside was identified as a targeted inhibitor of PDHB with antitumor effects.\",\n      \"method\": \"PDHB overexpression in HCC cells in vitro and xenograft in vivo, ChIP/promoter-binding assay for SLC2A1/GPI/PKM2, metabolic assays, drug resistance assay, in vivo combination treatment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies promoter binding, in vivo validation; single lab, mechanistic details from abstract are limited\",\n      \"pmids\": [\"39922943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGDHL (α-ketoglutarate dehydrogenase complex subunit) physically interacts with PDHB in gastric cancer cells; disruption of this interaction via miR-1343-3p-mediated OGDHL downregulation destabilizes PDHB, reduces pyruvate oxidative decarboxylation, and decreases acetyl-CoA and ATP production, inhibiting cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) confirming OGDHL–PDHB interaction, RIP for miRNA–mRNA interaction, Western blot for PDHB protein stability, ELISA and ATP detection, siRNA knockdown, xenograft in vivo\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishes protein interaction, functional metabolic readouts in vitro and in vivo; single lab\",\n      \"pmids\": [\"41420718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"PDH phosphate (PDHb) phosphatase in rat brain copurifies with mitochondrial marker enzymes and is located in mitochondria; the enzyme shows saturable kinetics, requires Mg2+ and Ca2+, is inhibited by NaF and K-phosphate, and functions to dephosphorylate and activate phosphorylated (inactive) PDH complex.\",\n      \"method\": \"Subcellular fractionation of rat brain, PDHb phosphatase activity assay using purified phospho-PDH complex as substrate, kinetic analysis, inhibitor studies\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzyme activity and subcellular localization by fractionation with marker enzymes; single lab, in vitro biochemistry\",\n      \"pmids\": [\"6300332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TGFβ signaling upregulates PDHB during definitive endoderm differentiation from human pluripotent stem cells, driving a metabolic switch with enhanced TCA cycle activity and oxidative phosphorylation. Mechanistically, PDHB-mediated pyruvate entry into the TCA cycle sustains intracellular ATP levels required for the activity of the BRG1-centered BAF chromatin remodeling complex, thereby promoting chromatin accessibility and endodermal gene programs.\",\n      \"method\": \"PDHB disruption during hPSC endoderm differentiation, metabolic assays (lactate, TCA metabolites, OXPHOS), ATP measurement, BRG1/BAF complex activity assay, chromatin accessibility (ATAC-seq or equivalent), endoderm marker expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional and metabolic assays linking PDHB to chromatin remodeling via ATP; single lab, abstract-level detail\",\n      \"pmids\": [\"41702907\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDHB (PDH E1β) is an essential structural and catalytic subunit of the pyruvate dehydrogenase complex (PDC) that forms an α2β2 heterotetramer with E1α; loss-of-function mutations in PDHB destabilize E1β and the entire PDC, abolishing conversion of pyruvate to acetyl-CoA and causing primary lactic acidosis; PDC activity is regulated by PHD3-mediated complex stabilization and by reversible phosphorylation/dephosphorylation of E1α catalyzed by PDH kinases and the mitochondria-localized PDHb phosphatase; PDHB levels are durably reduced under prolonged hypoxia to sustain the Warburg-like glycolytic state in cancer cells; additionally, PDHB interacts with OGDHL and, in some contexts, binds glycolytic gene promoters to regulate metabolic reprogramming, and its TGFβ-driven upregulation during endoderm differentiation supplies ATP for BRG1-dependent chromatin remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDHB encodes the E1β subunit of the mitochondrial pyruvate dehydrogenase complex (PDC), which assembles with E1α into an α2β2 heterotetramer to catalyze the oxidative decarboxylation of pyruvate to acetyl-CoA, the committed entry of glycolytic carbon into the TCA cycle [#4, #6]. Recessive loss-of-function missense mutations in PDHB reduce E1β immunoreactivity and abolish PDC activity, causing primary PDH complex deficiency that can present as Leigh syndrome; complementation with wild-type PDHB restores enzyme activity in patient fibroblasts, and structural and stability analyses show that pathogenic substitutions disrupt inter-subunit contacts and K+ ion coordination required for tetramer assembly, with E1β destabilization in turn destabilizing E1α [#2, #3, #6, #7]. The complex is stabilized post-translationally through physical interaction of PDHB with the prolyl-hydroxylase PHD3, which is required to maintain functional PDC and cellular PDH activity [#0], while a mitochondrial PDH phosphatase reactivates the phosphorylated, inactive complex [#12]. Beyond its canonical catalytic role, PDHB is a node in metabolic reprogramming: its levels are durably reduced under prolonged hypoxia to sustain a glycolytic Warburg-like state, and PDHB is itself regulated by miR-146b-5p and stabilized through interaction with OGDHL, with manipulation of PDHB altering glycolysis, acetyl-CoA/ATP output, and tumor growth in breast, colorectal, gastric, and hepatocellular cancers [#1, #8, #10, #11]. In hepatocellular carcinoma PDHB binds the promoters of glycolytic genes (SLC2A1, GPI, PKM2) to drive their transcription [#10], and during TGFβ-driven endoderm differentiation PDHB-supplied ATP supports BRG1/BAF chromatin remodeling and endodermal gene programs [#13]. Neuronal knockdown of Drosophila PDHB impairs lifespan, locomotion, neuromuscular junction morphology, and mitochondrial integrity, underscoring its requirement for neuronal energy metabolism [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The structural basis for how E1β assembles and what stabilizes the catalytic core was unknown; the archaeal E1β crystal structure defined the GPhiXXG helix-helix motif mediating the E1α–E1β interface and showed E1β rearranges and self-associates in the absence of E1α.\",\n      \"evidence\": \"X-ray crystallography of archaeal E1β with light scattering and analytical ultracentrifugation, compared to human and P. putida heterotetramers\",\n      \"pmids\": [\"11724561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure is of an archaeal ortholog, not human PDHB\", \"Does not address regulation of assembly in cells\", \"Catalytic mechanism within the assembled tetramer not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Whether PDHB mutations directly cause PDH deficiency rather than being incidental variants was unresolved; complementation of patient fibroblasts with wild-type PDHB restored PDC activity, establishing PDHB loss-of-function as a direct genetic cause.\",\n      \"evidence\": \"Mutation sequencing, immunoblot for E1β, and functional complementation by wild-type PDHB transfection in patient fibroblasts\",\n      \"pmids\": [\"15138885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Per-mutation structural mechanism not defined\", \"Does not address tissue-specific phenotype variability\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"How specific PDHB point mutations cause deficiency was unclear; a mutation series with structural modeling showed pathogenic substitutions disrupt inter-subunit contacts and K+ coordination needed for E1β stability and α2β2 assembly, and confirmed recessive inheritance.\",\n      \"evidence\": \"PDHB sequencing, PDC activity assays in lymphocytes and fibroblasts, immunoblot, and computational structural modeling\",\n      \"pmids\": [\"18164639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of mutant assembly\", \"Modeling not validated by experimental structures of mutants\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether E1β instability affects the partner subunit was unknown; PDHB mutations causing Leigh syndrome reduced both E1α and E1β protein levels, demonstrating that E1β destabilization collapses the entire E1 heterodimer.\",\n      \"evidence\": \"PDHB sequencing, PDHc/E1 activity assays in fibroblasts and muscle, immunoblot for E1α and E1β\",\n      \"pmids\": [\"19924563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No complementation performed\", \"Mechanism of co-degradation not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Continued discovery of pathogenic alleles; the c.575G>T (p.Arg192Leu) variant was shown to reduce PDHB stability and PDH activity in cells, confirming pathogenicity.\",\n      \"evidence\": \"Whole exome sequencing plus recombinant expression of wild-type and mutant PDHB in 293T cells with Western blot and PDH activity assay\",\n      \"pmids\": [\"40050878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient, single mutation\", \"Stability mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 1983,\n      \"claim\": \"The enzyme reactivating the phosphorylated PDC and its location were unresolved; PDHb phosphatase was localized to mitochondria and shown to dephosphorylate and activate inactive phospho-PDH in a Mg2+/Ca2+-dependent manner.\",\n      \"evidence\": \"Subcellular fractionation of rat brain with marker enzymes, phosphatase activity assay on purified phospho-PDH substrate, kinetic and inhibitor studies\",\n      \"pmids\": [\"6300332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in rat brain, not human\", \"Does not address regulation by upstream signals\", \"PDHB subunit-specific contribution to phosphatase substrate not isolated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How PDC stability is maintained beyond intrinsic assembly was unknown; PHD3 was identified as a physical PDHB interactor required to maintain PDC stability and activity, independent of subunit expression or phosphorylation, linking complex stability to hypoxic cell-death resistance.\",\n      \"evidence\": \"Proteomic interactor identification, Co-IP, PHD3 knockdown/knockout in MEFs and MCF7 cells with PDH activity assays and immunoblots\",\n      \"pmids\": [\"25088999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hydroxylation site/mechanism on PDC not defined\", \"Single lab\", \"Direct vs indirect stabilization not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether PDHB levels actively shape the cancer glycolytic state was unknown; prolonged hypoxia durably reduced PDHB to sustain a Warburg-like state, and PDHB manipulation bidirectionally altered PDH activity and tumor growth in vivo.\",\n      \"evidence\": \"siRNA knockdown and stable overexpression in cancer cells, PDH activity assays, xenograft growth assays, metabolic profiling\",\n      \"pmids\": [\"29436427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of durable suppression not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"How PDHB is downregulated in cancer was partly unresolved; miR-146b-5p was shown to directly target the PDHB 3'-UTR, and PDHB re-expression reversed the miRNA's oncogenic effects on growth, invasion, and glycolysis.\",\n      \"evidence\": \"miRNA gain/loss-of-function, 3'-UTR luciferase reporter, PDHB rescue, growth/invasion/glycolysis assays, xenograft in colorectal cancer\",\n      \"pmids\": [\"28560062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Other regulatory inputs not surveyed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Non-canonical functions of PDHB were unknown; PDHB was found to bind glycolytic gene promoters (SLC2A1, GPI, PKM2) to drive their transcription and contribute to sorafenib resistance in HCC, with isoacteoside identified as an inhibitor.\",\n      \"evidence\": \"PDHB overexpression in HCC cells and xenografts, ChIP/promoter-binding assays, metabolic and drug-resistance assays, in vivo combination treatment\",\n      \"pmids\": [\"39922943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear/chromatin localization of a mitochondrial enzyme not defined\", \"Direct DNA binding vs co-factor recruitment not resolved\", \"Single lab, abstract-level mechanistic detail\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A new PDHB stabilizing partner was identified; OGDHL physically interacts with PDHB in gastric cancer, and disrupting this interaction destabilizes PDHB, reduces pyruvate decarboxylation, and lowers acetyl-CoA/ATP, impairing proliferation.\",\n      \"evidence\": \"Co-IP for OGDHL–PDHB, RIP for miRNA–mRNA, immunoblot for PDHB stability, ELISA/ATP assays, siRNA knockdown, xenograft\",\n      \"pmids\": [\"41420718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of OGDHL–PDHB interaction unknown\", \"Reciprocal validation limited\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Whether PDHB-derived energy metabolism feeds developmental chromatin programs was unknown; TGFβ-induced PDHB during endoderm differentiation supplies ATP that sustains BRG1/BAF chromatin remodeling and endodermal gene activation.\",\n      \"evidence\": \"PDHB disruption during hPSC endoderm differentiation, metabolic/OXPHOS/ATP assays, BRG1/BAF activity and chromatin accessibility assays, marker expression\",\n      \"pmids\": [\"41702907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect link between ATP and BAF activity not fully isolated\", \"Single lab, abstract-level detail\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The in vivo neuronal requirement for PDHB was tested; pan-neuronal knockdown of Drosophila PDHB shortened lifespan and impaired locomotion, NMJ morphology, mitochondrial integrity, and axon targeting, establishing its necessity for neuronal energy metabolism.\",\n      \"evidence\": \"Tissue-specific RNAi in Drosophila neurons, lifespan/locomotor assays, confocal imaging of NMJs and mitochondria, photoreceptor axon analysis\",\n      \"pmids\": [\"29501567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Drosophila model; human neuronal relevance inferred\", \"Cell-autonomous metabolic cause vs developmental defect not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a canonically mitochondrial E1β subunit reaches gene promoters and whether its chromatin-associated and complex-stabilizing functions are mechanistically separable from its catalytic role remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PDHB on DNA\", \"Nuclear import/localization mechanism undefined\", \"Interplay between PHD3, OGDHL stabilization, and catalytic activity not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [2, 4, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 6]}\n    ],\n    \"complexes\": [\"pyruvate dehydrogenase complex\"],\n    \"partners\": [\"PHD3\", \"OGDHL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}