{"gene":"PDP1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2014,"finding":"K202 acetylation of PDP1 by mitochondrial acetyltransferase ACAT1 inhibits PDP1 activity by dissociating its substrate PDHA1, while SIRT3-mediated deacetylation reverses this inhibition. Additionally, Y381 phosphorylation of PDP1 dissociates SIRT3 from the pyruvate dehydrogenase complex (PDC) and recruits ACAT1, creating a hierarchical post-translational regulatory mechanism that controls PDC activity.","method":"In vitro acetylation/deacetylation assays, co-immunoprecipitation, site-directed mutagenesis, mass spectrometry, knockdown experiments with defined biochemical readouts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, Co-IP, in vitro assays, MS), specific residues identified, upstream writers/erasers characterized in single rigorous study","pmids":["24486017"],"is_preprint":false},{"year":2009,"finding":"A null mutation in PDP1 (homozygous c.277G>T, p.E93X nonsense mutation) completely abolishes PDP1 protein in mitochondria and causes failure to activate the PDH complex; native PDHc activity could be restored by addition of recombinant PDP1 or PDP2, demonstrating PDP1's direct phosphatase role in PDHc activation and identifying PDP2 as a compensatory isoform.","method":"Immunoblotting, enzymatic reconstitution with recombinant PDP1/PDP2, fibroblast biochemical assays, genetic mutation identification","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reconstitution with recombinant enzyme, null mutation with defined biochemical phenotype, multiple orthogonal methods in single study","pmids":["19184109"],"is_preprint":false},{"year":2021,"finding":"Rheb physically associates with PDP1 (PDH phosphatase), enhancing PDP1 activity and its association with the catalytic E1α-subunit of PDH, thereby reducing PDH phosphorylation and increasing PDH activity to support neuronal ATP production in response to synaptic activity.","method":"Co-immunoprecipitation, cell-type-specific gain- and loss-of-function genetic models, PDH phosphorylation/activity assays, acetyl-CoA and ATP measurements","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple genetic models (gain and loss of function), multiple biochemical readouts in single rigorous study","pmids":["33725483"],"is_preprint":false},{"year":2022,"finding":"PDP1 supports HIF-1 transcriptional activity under hypoxia by maintaining acetyl-CoA production through PDH activation, which sustains histone H3 acetylation at HIF-1 target gene promoters and enables HIF-1 binding to hypoxia-response elements; PDP1 depletion reduces histone acetylation and HIF-1 target gene expression without affecting HIF-1α protein levels or nuclear accumulation.","method":"siRNA knockdown, chromatin immunoprecipitation (ChIP), luciferase reporter assays, acetate/HDAC inhibitor rescue experiments, HIF-1α interaction assays","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter assays, chemical rescue), mechanistic pathway placed, single lab","pmids":["36453802"],"is_preprint":false},{"year":2023,"finding":"PDP1 acts as a scaffold protein that enhances BRAF and MEK1 interaction and activates MAPK signaling in KRAS-mutant colorectal cancer cells, promoting tumor progression through a mechanism distinct from its phosphatase activity on PDH. Transcription factor KLF5 drives PDP1 upregulation in KRAS-mutant CRC.","method":"Co-immunoprecipitation, in vitro and in vivo functional experiments, CRISPR screens, endogenous protein tagging, knockdown/overexpression studies","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating scaffold function, in vivo validation, single lab with multiple methods","pmids":["38849010"],"is_preprint":false},{"year":2023,"finding":"FLT3-ITD induces PDP1 expression through the RAS signaling axis in acute myeloid leukemia cells, and PDP1 functions as an activator of the pyruvate dehydrogenase complex to enhance oxidative glucose metabolism and maintain respiratory capacity; PDP1 knockdown reduces cellular respiration and impairs proliferation specifically in FLT3-ITD-positive cells.","method":"NMR metabolic profiling, genome-wide CRISPR screens, endogenous protein tagging, siRNA knockdown, respiratory capacity measurements, in vivo patient-derived blast experiments","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CRISPR screen, NMR, in vivo), genetic pathway established via CRISPR/knockdown with defined metabolic readouts","pmids":["37935978"],"is_preprint":false},{"year":2021,"finding":"Mitochondrial complex I defects decrease PDP1 activity through the [Ca2+]m-PDP1-PDH axis, reducing nuclear PDH and consequently decreasing histone acetylation at DNA damage repair sites, promoting radioresistance in colorectal cancer cells.","method":"Western blotting, NDUFS1 overexpression, in vivo tumor models, nuclear fractionation, histone acetylation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — defined pathway placement with gain-of-function rescue, multiple readouts, single lab","pmids":["34489398"],"is_preprint":false},{"year":2010,"finding":"PDP1/PPAPDC2 (a distinct gene encoding an integral membrane lipid phosphatase, PPAPDC2) preferentially hydrolyzes polyisoprenoid diphosphates (FPP, GGPP) in vitro; localizes to the endoplasmic reticulum and nuclear envelope in mammalian cells; overexpression depletes FPP pools in yeast causing sterol auxotrophy and decreases protein isoprenylation in mammalian cells, causing defects in cell growth and cytoskeletal organization via dysregulation of Rho family GTPases.","method":"Tandem mass spectrometry assays, recombinant enzyme in vitro assays, yeast overexpression growth/sterol assays, subcellular fractionation/localization, isoprenylation assays in mammalian cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic reconstitution with defined substrates, complementary in vivo functional assays, but this is PPAPDC2 (alias PDP1), a different protein from pyruvate dehydrogenase phosphatase PDP1; included as it shares the HGNC symbol PDP1/PPAPDC2","pmids":["20110354"],"is_preprint":false},{"year":2019,"finding":"A novel biallelic frameshift mutation (c.575dupT, p.L192FfsX5) in PDP1 causes absent PDP1 protein and functional pyruvate dehydrogenase complex deficiency, with low PDC activities in lymphocytes and fibroblasts; unexpectedly, BCKDH activity was also reduced in fibroblasts, suggesting a potential shared regulatory function.","method":"Genetic sequencing, immunoblotting, enzymatic activity assays in fibroblasts and lymphocytes","journal":"JIMD reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — null mutation with defined biochemical phenotype, multiple enzyme assays, single clinical case study","pmids":["31392110"],"is_preprint":false},{"year":2022,"finding":"miR-18a-3p directly targets PDP1 mRNA (validated by luciferase reporter assay) and negatively regulates PDP1 expression; PDP1 upregulation reverses the suppressive effect of miR-18a-3p on inflammatory cytokine secretion and matrix metalloproteinase levels in IL-1β-stimulated chondrocytes.","method":"Luciferase reporter assay, RT-qPCR, ELISA, western blotting, in vivo rat OA model","journal":"The journal of physiological sciences : JPS","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding validated by luciferase assay, rescue experiments confirm mechanism, single lab","pmids":["35148687"],"is_preprint":false}],"current_model":"PDP1 (pyruvate dehydrogenase phosphatase catalytic subunit 1) is a mitochondrial phosphatase that dephosphorylates and activates the pyruvate dehydrogenase complex (PDC), with its activity regulated by hierarchical post-translational modifications: ACAT1-mediated K202 acetylation inhibits PDP1 by dissociating PDHA1 substrate, SIRT3-mediated deacetylation restores activity, and Y381 phosphorylation toggles recruitment between ACAT1 and SIRT3; upstream, Rheb physically associates with PDP1 to enhance its activity in response to neuronal activity, FLT3-ITD/RAS signaling induces PDP1 expression to support oxidative metabolism and drug resistance in AML, PDP1 sustains HIF-1 transcriptional activity through acetyl-CoA-dependent chromatin acetylation, and PDP1 can act as a non-enzymatic scaffold enhancing BRAF-MEK1 interaction in KRAS-mutant cancers."},"narrative":{"mechanistic_narrative":"PDP1 is a mitochondrial phosphatase that dephosphorylates and activates the pyruvate dehydrogenase complex (PDC), serving as a key node that couples glucose oxidation to cellular energy demand [PMID:19184109, PMID:33725483]. A null mutation that abolishes PDP1 protein eliminates PDC activation, and native activity is restored by recombinant PDP1 (with PDP2 acting as a compensatory isoform), establishing PDP1's direct catalytic role on the PDHA1 (E1α) subunit [PMID:19184109]. PDP1 activity is governed by hierarchical post-translational modifications: ACAT1-mediated K202 acetylation inhibits PDP1 by dissociating its PDHA1 substrate, SIRT3-mediated deacetylation reverses this, and Y381 phosphorylation toggles the recruitment of ACAT1 versus SIRT3 to the complex [PMID:24486017]. Upstream regulators tune this axis in distinct physiological contexts: Rheb physically associates with PDP1 to enhance its activity and PDH dephosphorylation in response to synaptic activity [PMID:33725483], while FLT3-ITD/RAS signaling induces PDP1 expression to sustain oxidative glucose metabolism, respiratory capacity, and proliferation in AML [PMID:37935978]. Beyond mitochondrial catabolism, PDP1-dependent PDH activation supplies acetyl-CoA that maintains histone H3 acetylation, sustaining HIF-1 transcriptional activity at hypoxia-response elements [PMID:36453802] and modulating histone acetylation at DNA damage repair sites [PMID:34489398]. PDP1 additionally functions non-enzymatically as a scaffold that enhances BRAF–MEK1 interaction and MAPK signaling in KRAS-mutant colorectal cancer [PMID:38849010]. Biallelic loss-of-function mutations in PDP1 cause pyruvate dehydrogenase complex deficiency [PMID:19184109, PMID:31392110]. Note that the alias PPAPDC2, an ER/nuclear-envelope polyisoprenoid diphosphate phosphatase sharing the HGNC symbol, is a distinct protein [PMID:20110354].","teleology":[{"year":2009,"claim":"Established that PDP1 is directly required for PDC activation in human cells, resolving whether its phosphatase activity is essential versus redundant.","evidence":"Identification of a homozygous nonsense mutation abolishing PDP1, with enzymatic reconstitution by recombinant PDP1/PDP2 in patient fibroblasts","pmids":["19184109"],"confidence":"High","gaps":["Did not define the post-translational regulation of PDP1 activity","Degree and physiological scope of PDP2 compensation unclear"]},{"year":2010,"claim":"Characterized PPAPDC2 (an alias sharing the PDP1/HGNC symbol) as a distinct ER/nuclear-envelope polyisoprenoid diphosphate phosphatase, flagging a symbol collision.","evidence":"Recombinant enzyme in vitro substrate assays, yeast sterol auxotrophy, and isoprenylation assays in mammalian cells","pmids":["20110354"],"confidence":"Medium","gaps":["This is a different protein from pyruvate dehydrogenase phosphatase PDP1","Endogenous physiological role of PPAPDC2 not established"]},{"year":2014,"claim":"Defined the hierarchical PTM logic controlling PDP1, showing how acetylation and tyrosine phosphorylation gate writer/eraser recruitment to the PDC.","evidence":"In vitro acetylation/deacetylation assays, Co-IP, site-directed mutagenesis (K202, Y381), and mass spectrometry","pmids":["24486017"],"confidence":"High","gaps":["Upstream kinase responsible for Y381 phosphorylation not identified","Physiological signals driving ACAT1/SIRT3 switching not mapped"]},{"year":2021,"claim":"Identified Rheb as a direct upstream activator linking neuronal/synaptic activity to PDP1-driven PDH activation and ATP production.","evidence":"Co-IP, cell-type-specific gain- and loss-of-function genetic models, PDH phosphorylation/activity and acetyl-CoA/ATP measurements","pmids":["33725483"],"confidence":"High","gaps":["Structural basis of Rheb-PDP1 association unknown","Whether Rheb effect is GTP-dependent not resolved here"]},{"year":2021,"claim":"Connected PDP1 to the nucleus by showing the [Ca2+]m-PDP1-PDH axis controls histone acetylation at DNA damage repair sites and radioresistance.","evidence":"Western blotting, NDUFS1 gain-of-function rescue, nuclear fractionation, histone acetylation assays, and in vivo tumor models","pmids":["34489398"],"confidence":"Medium","gaps":["Mechanism of nuclear PDH/PDP1 trafficking not detailed","Single lab; direct PDP1 contribution versus complex-level effect not separated"]},{"year":2022,"claim":"Extended PDP1's metabolic role to epigenetic control of transcription, showing acetyl-CoA supply sustains HIF-1 target gene expression independent of HIF-1α stability.","evidence":"siRNA knockdown, ChIP, luciferase reporters, and acetate/HDAC-inhibitor rescue experiments","pmids":["36453802"],"confidence":"High","gaps":["Acetyltransferase(s) acting on H3 at HIF-1 promoters not identified","Generality across cell types beyond those tested unclear"]},{"year":2022,"claim":"Placed PDP1 under microRNA control, showing miR-18a-3p directly represses PDP1 with downstream effects on chondrocyte inflammatory responses.","evidence":"Luciferase reporter binding validation, RT-qPCR, ELISA, and an in vivo rat OA model","pmids":["35148687"],"confidence":"Medium","gaps":["Mechanistic link between PDP1 level and cytokine/MMP output not fully resolved","Single lab"]},{"year":2023,"claim":"Demonstrated oncogenic dependency: FLT3-ITD/RAS signaling induces PDP1 to maintain oxidative metabolism and proliferation in AML.","evidence":"Genome-wide CRISPR screens, NMR metabolic profiling, siRNA knockdown, respiratory measurements, and in vivo patient-derived blast experiments","pmids":["37935978"],"confidence":"High","gaps":["Direct transcriptional effectors downstream of RAS driving PDP1 not pinpointed","Therapeutic window of PDP1 inhibition in AML untested"]},{"year":2023,"claim":"Revealed a moonlighting, phosphatase-independent function of PDP1 as a scaffold promoting BRAF-MEK1 interaction and MAPK signaling in KRAS-mutant cancer.","evidence":"Co-IP, CRISPR screens, endogenous protein tagging, in vitro and in vivo functional assays, and identification of KLF5 as a transcriptional driver","pmids":["38849010"],"confidence":"Medium","gaps":["Structural basis of the scaffold interaction unresolved","How a mitochondrial enzyme accesses cytosolic BRAF-MEK1 not explained","Single lab"]},{"year":null,"claim":"How PDP1's distinct activities—mitochondrial phosphatase, acetyl-CoA-dependent epigenetic regulator, and cytosolic MAPK scaffold—are spatially and physiologically partitioned within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling mitochondrial, nuclear, and cytosolic pools","Kinase for Y381 and signals controlling localization unknown","No structural model of PDP1 in any of its complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]}],"complexes":["pyruvate dehydrogenase complex (PDC)"],"partners":["PDHA1","ACAT1","SIRT3","RHEB","BRAF","MAP2K1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IY26","full_name":"Polyisoprenoid diphosphate/phosphate phosphohydrolase PLPP6","aliases":["Lipid phosphatase-related protein-B","LPRP-B","PA-PSP","Phosphatidic acid phosphatase type 2 domain-containing protein 2","PPAP2 domain-containing protein 2","Phospholipid phosphatase 6","Presqualene diphosphate phosphatase","Type 1 polyisoprenoid diphosphate phosphatase"],"length_aa":295,"mass_kda":32.2,"function":"Magnesium-independent polyisoprenoid diphosphatase that catalyzes the sequential dephosphorylation of presqualene, farnesyl, geranyl and geranylgeranyl diphosphates (PubMed:16464866, PubMed:19220020, PubMed:20110354). Functions in the innate immune response through the dephosphorylation of presqualene diphosphate which acts as a potent inhibitor of the signaling pathways contributing to polymorphonuclear neutrophils activation (PubMed:16464866, PubMed:23568778). May regulate the biosynthesis of cholesterol and related sterols by dephosphorylating presqualene and farnesyl diphosphate, two key intermediates in this biosynthetic pathway (PubMed:20110354). May also play a role in protein prenylation by acting on farnesyl diphosphate and its derivative geranylgeranyl diphosphate, two precursors for the addition of isoprenoid anchors to membrane proteins (PubMed:20110354). Has a lower activity towards phosphatidic acid (PA), but through phosphatidic acid dephosphorylation may participate in the biosynthesis of phospholipids and triacylglycerols (PubMed:18930839). May also act on ceramide-1-P, lysophosphatidic acid (LPA) and sphing-4-enine 1-phosphate/sphingosine-1-phosphate (PubMed:18930839, PubMed:20110354)","subcellular_location":"Endoplasmic reticulum membrane; Nucleus envelope; Nucleus inner membrane","url":"https://www.uniprot.org/uniprotkb/Q8IY26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDP1","total_profiled":1310},"omim":[{"mim_id":"617835","title":"PYRUVATE DEHYDROGENASE PHOSPHATASE REGULATORY SUBUNIT; PDPR","url":"https://www.omim.org/entry/617835"},{"mim_id":"616302","title":"FORKHEAD BOX K1; FOXK1","url":"https://www.omim.org/entry/616302"},{"mim_id":"615499","title":"PYRUVATE DEHYDROGENASE PHOSPHATASE CATALYTIC SUBUNIT 2; PDP2","url":"https://www.omim.org/entry/615499"},{"mim_id":"608782","title":"PYRUVATE DEHYDROGENASE PHOSPHATASE DEFICIENCY; PDHPD","url":"https://www.omim.org/entry/608782"},{"mim_id":"605993","title":"PYRUVATE DEHYDROGENASE PHOSPHATASE, CATALYTIC SUBUNIT 1; PDP1","url":"https://www.omim.org/entry/605993"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDP1"},"hgnc":{"alias_symbol":["PDP","PDH","PPM2A"],"prev_symbol":["PPM2C"]},"alphafold":{"accession":"Q8IY26","domains":[{"cath_id":"-","chopping":"154-294","consensus_level":"high","plddt":86.1782,"start":154,"end":294}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IY26","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IY26-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IY26-F1-predicted_aligned_error_v6.png","plddt_mean":72.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDP1","jax_strain_url":"https://www.jax.org/strain/search?query=PDP1"},"sequence":{"accession":"Q8IY26","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IY26.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IY26/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IY26"}},"corpus_meta":[{"pmid":"12581523","id":"PMC_12581523","title":"vrille, Pdp1, and dClock form a second feedback loop in the Drosophila circadian clock.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12581523","citation_count":426,"is_preprint":false},{"pmid":"24486017","id":"PMC_24486017","title":"Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24486017","citation_count":255,"is_preprint":false},{"pmid":"9688676","id":"PMC_9688676","title":"Regulation of skeletal muscle glycogen phosphorylase and PDH at varying exercise power outputs.","date":"1998","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9688676","citation_count":144,"is_preprint":false},{"pmid":"9887028","id":"PMC_9887028","title":"PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH.","date":"1999","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9887028","citation_count":131,"is_preprint":false},{"pmid":"11701428","id":"PMC_11701428","title":"Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet.","date":"2001","source":"American journal of physiology. 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guinea-pigs and marmosets: species-dependent effects of the soman simulator, pinacolyl dimethylphosphinate (PDP).","date":"1988","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2896771","citation_count":13,"is_preprint":false},{"pmid":"38849010","id":"PMC_38849010","title":"PDP1 promotes KRAS mutant colorectal cancer progression by serving as a scaffold for BRAF and MEK1.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38849010","citation_count":12,"is_preprint":false},{"pmid":"34749282","id":"PMC_34749282","title":"Evaluation of immune effect of Streptococcus suis biofilm-associated protein PDH.","date":"2021","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34749282","citation_count":12,"is_preprint":false},{"pmid":"31392110","id":"PMC_31392110","title":"A novel null mutation in the pyruvate dehydrogenase phosphatase catalytic subunit gene (PDP1) causing pyruvate dehydrogenase complex deficiency.","date":"2019","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/31392110","citation_count":12,"is_preprint":false},{"pmid":"33808434","id":"PMC_33808434","title":"LDH and PDH Activities in the Ischemic Brain and the Effect of Reperfusion-An Ex Vivo MR Study in Rat Brain Slices Using Hyperpolarized [1-13C]Pyruvate.","date":"2021","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/33808434","citation_count":12,"is_preprint":false},{"pmid":"11757583","id":"PMC_11757583","title":"A case of PDH-E1 alpha mosaicism in a male patient with severe metabolic lactic acidosis.","date":"2001","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/11757583","citation_count":12,"is_preprint":false},{"pmid":"28969796","id":"PMC_28969796","title":"Induction of the PDH bypass and upregulation of the ALDH7B4 in plants treated with herbicides inhibiting amino acid biosynthesis.","date":"2017","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/28969796","citation_count":12,"is_preprint":false},{"pmid":"1823925","id":"PMC_1823925","title":"Primary structure and relative potency of an analog of beta-PDH (pigment-dispersing hormone) from the crayfish Procambarus clarkii.","date":"1991","source":"Pigment cell research","url":"https://pubmed.ncbi.nlm.nih.gov/1823925","citation_count":12,"is_preprint":false},{"pmid":"10767328","id":"PMC_10767328","title":"Sequential deletion of C-terminal amino acids of the E(1)alpha component of the pyruvate dehydrogenase (PDH) complex leads to reduced steady-state levels of functional E(1)alpha(2)beta(2) tetramers: implications for patients with PDH deficiency.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10767328","citation_count":12,"is_preprint":false},{"pmid":"34696348","id":"PMC_34696348","title":"Application Route and Immune Status of the Host Determine Safety and Oncolytic Activity of Oncolytic Coxsackievirus B3 Variant PD-H.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/34696348","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51743,"output_tokens":2797,"usd":0.098592,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10167,"output_tokens":3471,"usd":0.068805,"stage2_stop_reason":"end_turn"},"total_usd":0.167397,"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\": \"K202 acetylation of PDP1 by mitochondrial acetyltransferase ACAT1 inhibits PDP1 activity by dissociating its substrate PDHA1, while SIRT3-mediated deacetylation reverses this inhibition. Additionally, Y381 phosphorylation of PDP1 dissociates SIRT3 from the pyruvate dehydrogenase complex (PDC) and recruits ACAT1, creating a hierarchical post-translational regulatory mechanism that controls PDC activity.\",\n      \"method\": \"In vitro acetylation/deacetylation assays, co-immunoprecipitation, site-directed mutagenesis, mass spectrometry, knockdown experiments with defined biochemical readouts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (mutagenesis, Co-IP, in vitro assays, MS), specific residues identified, upstream writers/erasers characterized in single rigorous study\",\n      \"pmids\": [\"24486017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A null mutation in PDP1 (homozygous c.277G>T, p.E93X nonsense mutation) completely abolishes PDP1 protein in mitochondria and causes failure to activate the PDH complex; native PDHc activity could be restored by addition of recombinant PDP1 or PDP2, demonstrating PDP1's direct phosphatase role in PDHc activation and identifying PDP2 as a compensatory isoform.\",\n      \"method\": \"Immunoblotting, enzymatic reconstitution with recombinant PDP1/PDP2, fibroblast biochemical assays, genetic mutation identification\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstitution with recombinant enzyme, null mutation with defined biochemical phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19184109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rheb physically associates with PDP1 (PDH phosphatase), enhancing PDP1 activity and its association with the catalytic E1α-subunit of PDH, thereby reducing PDH phosphorylation and increasing PDH activity to support neuronal ATP production in response to synaptic activity.\",\n      \"method\": \"Co-immunoprecipitation, cell-type-specific gain- and loss-of-function genetic models, PDH phosphorylation/activity assays, acetyl-CoA and ATP measurements\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple genetic models (gain and loss of function), multiple biochemical readouts in single rigorous study\",\n      \"pmids\": [\"33725483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDP1 supports HIF-1 transcriptional activity under hypoxia by maintaining acetyl-CoA production through PDH activation, which sustains histone H3 acetylation at HIF-1 target gene promoters and enables HIF-1 binding to hypoxia-response elements; PDP1 depletion reduces histone acetylation and HIF-1 target gene expression without affecting HIF-1α protein levels or nuclear accumulation.\",\n      \"method\": \"siRNA knockdown, chromatin immunoprecipitation (ChIP), luciferase reporter assays, acetate/HDAC inhibitor rescue experiments, HIF-1α interaction assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter assays, chemical rescue), mechanistic pathway placed, single lab\",\n      \"pmids\": [\"36453802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PDP1 acts as a scaffold protein that enhances BRAF and MEK1 interaction and activates MAPK signaling in KRAS-mutant colorectal cancer cells, promoting tumor progression through a mechanism distinct from its phosphatase activity on PDH. Transcription factor KLF5 drives PDP1 upregulation in KRAS-mutant CRC.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo functional experiments, CRISPR screens, endogenous protein tagging, knockdown/overexpression studies\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating scaffold function, in vivo validation, single lab with multiple methods\",\n      \"pmids\": [\"38849010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FLT3-ITD induces PDP1 expression through the RAS signaling axis in acute myeloid leukemia cells, and PDP1 functions as an activator of the pyruvate dehydrogenase complex to enhance oxidative glucose metabolism and maintain respiratory capacity; PDP1 knockdown reduces cellular respiration and impairs proliferation specifically in FLT3-ITD-positive cells.\",\n      \"method\": \"NMR metabolic profiling, genome-wide CRISPR screens, endogenous protein tagging, siRNA knockdown, respiratory capacity measurements, in vivo patient-derived blast experiments\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CRISPR screen, NMR, in vivo), genetic pathway established via CRISPR/knockdown with defined metabolic readouts\",\n      \"pmids\": [\"37935978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mitochondrial complex I defects decrease PDP1 activity through the [Ca2+]m-PDP1-PDH axis, reducing nuclear PDH and consequently decreasing histone acetylation at DNA damage repair sites, promoting radioresistance in colorectal cancer cells.\",\n      \"method\": \"Western blotting, NDUFS1 overexpression, in vivo tumor models, nuclear fractionation, histone acetylation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — defined pathway placement with gain-of-function rescue, multiple readouts, single lab\",\n      \"pmids\": [\"34489398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDP1/PPAPDC2 (a distinct gene encoding an integral membrane lipid phosphatase, PPAPDC2) preferentially hydrolyzes polyisoprenoid diphosphates (FPP, GGPP) in vitro; localizes to the endoplasmic reticulum and nuclear envelope in mammalian cells; overexpression depletes FPP pools in yeast causing sterol auxotrophy and decreases protein isoprenylation in mammalian cells, causing defects in cell growth and cytoskeletal organization via dysregulation of Rho family GTPases.\",\n      \"method\": \"Tandem mass spectrometry assays, recombinant enzyme in vitro assays, yeast overexpression growth/sterol assays, subcellular fractionation/localization, isoprenylation assays in mammalian cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic reconstitution with defined substrates, complementary in vivo functional assays, but this is PPAPDC2 (alias PDP1), a different protein from pyruvate dehydrogenase phosphatase PDP1; included as it shares the HGNC symbol PDP1/PPAPDC2\",\n      \"pmids\": [\"20110354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A novel biallelic frameshift mutation (c.575dupT, p.L192FfsX5) in PDP1 causes absent PDP1 protein and functional pyruvate dehydrogenase complex deficiency, with low PDC activities in lymphocytes and fibroblasts; unexpectedly, BCKDH activity was also reduced in fibroblasts, suggesting a potential shared regulatory function.\",\n      \"method\": \"Genetic sequencing, immunoblotting, enzymatic activity assays in fibroblasts and lymphocytes\",\n      \"journal\": \"JIMD reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — null mutation with defined biochemical phenotype, multiple enzyme assays, single clinical case study\",\n      \"pmids\": [\"31392110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-18a-3p directly targets PDP1 mRNA (validated by luciferase reporter assay) and negatively regulates PDP1 expression; PDP1 upregulation reverses the suppressive effect of miR-18a-3p on inflammatory cytokine secretion and matrix metalloproteinase levels in IL-1β-stimulated chondrocytes.\",\n      \"method\": \"Luciferase reporter assay, RT-qPCR, ELISA, western blotting, in vivo rat OA model\",\n      \"journal\": \"The journal of physiological sciences : JPS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding validated by luciferase assay, rescue experiments confirm mechanism, single lab\",\n      \"pmids\": [\"35148687\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDP1 (pyruvate dehydrogenase phosphatase catalytic subunit 1) is a mitochondrial phosphatase that dephosphorylates and activates the pyruvate dehydrogenase complex (PDC), with its activity regulated by hierarchical post-translational modifications: ACAT1-mediated K202 acetylation inhibits PDP1 by dissociating PDHA1 substrate, SIRT3-mediated deacetylation restores activity, and Y381 phosphorylation toggles recruitment between ACAT1 and SIRT3; upstream, Rheb physically associates with PDP1 to enhance its activity in response to neuronal activity, FLT3-ITD/RAS signaling induces PDP1 expression to support oxidative metabolism and drug resistance in AML, PDP1 sustains HIF-1 transcriptional activity through acetyl-CoA-dependent chromatin acetylation, and PDP1 can act as a non-enzymatic scaffold enhancing BRAF-MEK1 interaction in KRAS-mutant cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDP1 is a mitochondrial phosphatase that dephosphorylates and activates the pyruvate dehydrogenase complex (PDC), serving as a key node that couples glucose oxidation to cellular energy demand [#1, #2]. A null mutation that abolishes PDP1 protein eliminates PDC activation, and native activity is restored by recombinant PDP1 (with PDP2 acting as a compensatory isoform), establishing PDP1's direct catalytic role on the PDHA1 (E1\\u03b1) subunit [#1]. PDP1 activity is governed by hierarchical post-translational modifications: ACAT1-mediated K202 acetylation inhibits PDP1 by dissociating its PDHA1 substrate, SIRT3-mediated deacetylation reverses this, and Y381 phosphorylation toggles the recruitment of ACAT1 versus SIRT3 to the complex [#0]. Upstream regulators tune this axis in distinct physiological contexts: Rheb physically associates with PDP1 to enhance its activity and PDH dephosphorylation in response to synaptic activity [#2], while FLT3-ITD/RAS signaling induces PDP1 expression to sustain oxidative glucose metabolism, respiratory capacity, and proliferation in AML [#5]. Beyond mitochondrial catabolism, PDP1-dependent PDH activation supplies acetyl-CoA that maintains histone H3 acetylation, sustaining HIF-1 transcriptional activity at hypoxia-response elements [#3] and modulating histone acetylation at DNA damage repair sites [#6]. PDP1 additionally functions non-enzymatically as a scaffold that enhances BRAF\\u2013MEK1 interaction and MAPK signaling in KRAS-mutant colorectal cancer [#4]. Biallelic loss-of-function mutations in PDP1 cause pyruvate dehydrogenase complex deficiency [#1, #8]. Note that the alias PPAPDC2, an ER/nuclear-envelope polyisoprenoid diphosphate phosphatase sharing the HGNC symbol, is a distinct protein [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that PDP1 is directly required for PDC activation in human cells, resolving whether its phosphatase activity is essential versus redundant.\",\n      \"evidence\": \"Identification of a homozygous nonsense mutation abolishing PDP1, with enzymatic reconstitution by recombinant PDP1/PDP2 in patient fibroblasts\",\n      \"pmids\": [\"19184109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the post-translational regulation of PDP1 activity\", \"Degree and physiological scope of PDP2 compensation unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Characterized PPAPDC2 (an alias sharing the PDP1/HGNC symbol) as a distinct ER/nuclear-envelope polyisoprenoid diphosphate phosphatase, flagging a symbol collision.\",\n      \"evidence\": \"Recombinant enzyme in vitro substrate assays, yeast sterol auxotrophy, and isoprenylation assays in mammalian cells\",\n      \"pmids\": [\"20110354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"This is a different protein from pyruvate dehydrogenase phosphatase PDP1\", \"Endogenous physiological role of PPAPDC2 not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the hierarchical PTM logic controlling PDP1, showing how acetylation and tyrosine phosphorylation gate writer/eraser recruitment to the PDC.\",\n      \"evidence\": \"In vitro acetylation/deacetylation assays, Co-IP, site-directed mutagenesis (K202, Y381), and mass spectrometry\",\n      \"pmids\": [\"24486017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream kinase responsible for Y381 phosphorylation not identified\", \"Physiological signals driving ACAT1/SIRT3 switching not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified Rheb as a direct upstream activator linking neuronal/synaptic activity to PDP1-driven PDH activation and ATP production.\",\n      \"evidence\": \"Co-IP, cell-type-specific gain- and loss-of-function genetic models, PDH phosphorylation/activity and acetyl-CoA/ATP measurements\",\n      \"pmids\": [\"33725483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Rheb-PDP1 association unknown\", \"Whether Rheb effect is GTP-dependent not resolved here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected PDP1 to the nucleus by showing the [Ca2+]m-PDP1-PDH axis controls histone acetylation at DNA damage repair sites and radioresistance.\",\n      \"evidence\": \"Western blotting, NDUFS1 gain-of-function rescue, nuclear fractionation, histone acetylation assays, and in vivo tumor models\",\n      \"pmids\": [\"34489398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear PDH/PDP1 trafficking not detailed\", \"Single lab; direct PDP1 contribution versus complex-level effect not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended PDP1's metabolic role to epigenetic control of transcription, showing acetyl-CoA supply sustains HIF-1 target gene expression independent of HIF-1\\u03b1 stability.\",\n      \"evidence\": \"siRNA knockdown, ChIP, luciferase reporters, and acetate/HDAC-inhibitor rescue experiments\",\n      \"pmids\": [\"36453802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase(s) acting on H3 at HIF-1 promoters not identified\", \"Generality across cell types beyond those tested unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed PDP1 under microRNA control, showing miR-18a-3p directly represses PDP1 with downstream effects on chondrocyte inflammatory responses.\",\n      \"evidence\": \"Luciferase reporter binding validation, RT-qPCR, ELISA, and an in vivo rat OA model\",\n      \"pmids\": [\"35148687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between PDP1 level and cytokine/MMP output not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated oncogenic dependency: FLT3-ITD/RAS signaling induces PDP1 to maintain oxidative metabolism and proliferation in AML.\",\n      \"evidence\": \"Genome-wide CRISPR screens, NMR metabolic profiling, siRNA knockdown, respiratory measurements, and in vivo patient-derived blast experiments\",\n      \"pmids\": [\"37935978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional effectors downstream of RAS driving PDP1 not pinpointed\", \"Therapeutic window of PDP1 inhibition in AML untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a moonlighting, phosphatase-independent function of PDP1 as a scaffold promoting BRAF-MEK1 interaction and MAPK signaling in KRAS-mutant cancer.\",\n      \"evidence\": \"Co-IP, CRISPR screens, endogenous protein tagging, in vitro and in vivo functional assays, and identification of KLF5 as a transcriptional driver\",\n      \"pmids\": [\"38849010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the scaffold interaction unresolved\", \"How a mitochondrial enzyme accesses cytosolic BRAF-MEK1 not explained\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PDP1's distinct activities\\u2014mitochondrial phosphatase, acetyl-CoA-dependent epigenetic regulator, and cytosolic MAPK scaffold\\u2014are spatially and physiologically partitioned within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling mitochondrial, nuclear, and cytosolic pools\", \"Kinase for Y381 and signals controlling localization unknown\", \"No structural model of PDP1 in any of its complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"pyruvate dehydrogenase complex (PDC)\"],\n    \"partners\": [\"PDHA1\", \"ACAT1\", \"SIRT3\", \"RHEB\", \"BRAF\", \"MAP2K1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}