PDHA1 encodes the somatic form of the pyruvate dehydrogenase E1 component subunit alpha (E1alpha), a mitochondrial matrix protein. Together with PDHB (E1beta) it assembles into the alpha2-beta2 heterotetrameric E1 component of the pyruvate dehydrogenase complex (PDC), the multienzyme assembly (E1, E2/DLAT, E3/DLD, plus the E3-binding protein) that catalyzes the committed, rate-limiting oxidative decarboxylation of pyruvate to acetyl-CoA and CO2 with reduction of NAD+ to NADH. The E1 alpha subunit carries the thiamine pyrophosphate (TPP)- and Mg2+-dependent active site and performs two consecutive steps: TPP-dependent decarboxylation of pyruvate to a hydroxyethyl-TPP intermediate, and reductive acetylation of the lipoyl group covalently attached to the E2 lipoyl domains. By converting pyruvate to acetyl-CoA, PDC forms the metabolic gateway that links cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle and lipogenesis. Enzyme activity is switched off by phosphorylation of conserved serine residues on E1alpha (Ser-232, Ser-293, Ser-300; sites 3, 1, 2) by pyruvate dehydrogenase kinases (PDKs) and switched back on by dephosphorylation by pyruvate dehydrogenase phosphatases (PDPs). The gene is X-linked, and pathogenic variants cause pyruvate dehydrogenase E1-alpha deficiency, the most common cause of PDC deficiency, presenting with primary lactic acidosis and neurological disease (including Leigh syndrome).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004739 pyruvate dehydrogenase (acetyl-transferring) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assertion of the core molecular function: pyruvate dehydrogenase (acetyl-transferring) activity (EC 1.2.4.1). This is the defining catalytic activity of the E1 alpha subunit and is independently confirmed by direct experimental annotations (EXP/IDA) on this protein. Reason: Correct and central function. E1alpha, with E1beta, catalyzes the TPP-dependent decarboxylation of pyruvate and reductive acetylation of the E2 lipoyl group. Supporting Evidence: PMID:19081061 The E1p component catalyzes the ThDP-mediated decarboxylation of pyruvate (Reaction 2) and the reductive acetylation of a lipoyl group PMID:3034892 the alpha subunit of human pyruvate dehydrogenase (EC 1.2.4.1), the E1 component of the pyruvate dehydrogenase complex |
| GO:0005759 mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that PDHA1 is active in the mitochondrial matrix. This is the established compartment of the PDH complex and is supported by the UniProt subcellular location. Reason: PDHA1 is synthesized with a mitochondrial import leader and functions in the matrix as part of the soluble PDH complex. Supporting Evidence: PMID:3034892 The protein is synthesized with a typical mitochondrial import leader file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that PDHA1 is involved in pyruvate decarboxylation to acetyl-CoA, the biological process carried out by the PDH complex. Consistent with direct experimental annotations. Reason: This is the core process to which the E1 catalytic activity contributes; the PDH complex converts pyruvate to acetyl-CoA and CO2. Supporting Evidence: PMID:19081061 The human pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to produce acetyl-CoA and NADH |
| GO:0045254 pyruvate dehydrogenase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assertion that PDHA1 is part of the pyruvate dehydrogenase complex. PDHA1 is a constitutive catalytic subunit of the PDC (as the E1 alpha subunit). Reason: PDHA1 forms the E1 heterotetramer with PDHB and is a core component of the multienzyme PDH complex. Supporting Evidence: PMID:19240034 The human pyruvate dehydrogenase complex (PDC) is a 9.5-megadalton catalytic machine that employs three catalytic components, i.e. pyruvate dehydrogenase (E1p) |
| GO:0004739 pyruvate dehydrogenase (acetyl-transferring) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assertion of pyruvate dehydrogenase activity, mapped from the EC 1.2.4.1 / RHEA:19189 / InterPro E1alpha signature. Redundant with the IBA and experimental MF annotations. Reason: Correctly captures the enzymatic function via EC/RHEA/InterPro mapping. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt EC=1.2.4.1 |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Automated location annotation derived from the UniProt subcellular location controlled vocabulary (mitochondrion matrix, SL-0170). Reason: Consistent with the curated UniProt subcellular location and the IBA matrix annotation. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assertion of involvement in pyruvate decarboxylation to acetyl-CoA, from the InterPro E1alpha signature. Redundant with the IBA and experimental process annotations. Reason: Correct process for the E1 subunit of the PDH complex. Supporting Evidence: PMID:19081061 catalyzes the oxidative decarboxylation of pyruvate to produce acetyl-CoA |
| GO:0016624 oxidoreductase activity, acting on the aldehyde or oxo group of donors, disulfide as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping to the general oxidoreductase class. This is the parent of the specific, EC-mapped pyruvate dehydrogenase activity (GO:0004739) already annotated to PDHA1, so it is correct but too general. Reason: Not wrong, but this broad oxidoreductase class is less informative than the specific EC 1.2.4.1 activity; replace with the specific term already supported experimentally. Proposed replacements: pyruvate dehydrogenase (acetyl-transferring) activity Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt EC=1.2.4.1 |
| GO:0045254 pyruvate dehydrogenase complex | IEA GO_REF:0000117 | ACCEPT | Summary: Automated (ARBA) assertion that PDHA1 is part of the pyruvate dehydrogenase complex. Redundant with IBA/IDA complex annotations. Reason: Correct complex assignment for the E1 alpha subunit. Supporting Evidence: PMID:19240034 pyruvate dehydrogenase (E1p) |
| GO:0005515 protein binding | IPI PMID:12651851 Structural basis for flip-flop action of thiamin pyrophospha... | REMOVE | Summary: IntAct IPI capturing the physical interaction of PDHA1 with PDHB (UniProtKB:P11177), derived from the human E1 crystal structure. This is the genuine intra-E1 alpha-beta subunit contact, but the bare "protein binding" term is uninformative; the biologically meaningful assertion (PDHA1 as part of the E1 heterotetramer / PDH complex) is already captured by GO:0045254. Reason: Bare protein binding is uninformative. The E1alpha-E1beta (PDHB) heterotetramer contact is a genuine subunit-assembly interaction within the pyruvate dehydrogenase complex, which is represented by the complex cellular-component annotations; the paper supports no more specific molecular function for PDHA1. Removal does not mean the interaction is false. Supporting Evidence: PMID:12651851 In alpha2beta2-heterotetrameric human pyruvate dehydrogenase |
| GO:0005515 protein binding | IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ... | REMOVE | Summary: IntAct IPI from a large-scale human mitochondrial protein interaction map (interactors PDHB/P11177 and IMMT/Q16891). Bare "protein binding" is uninformative; PDHB interaction is already captured by complex membership. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for PDHA1. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:29128334 A Map of Human Mitochondrial Protein Interactions |
| GO:0005515 protein binding | IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive... | REMOVE | Summary: IntAct IPI (interactor PDK1/Q15118) from a MAC-tag AP-MS/BioID interaction and localization mapping study. The PDK1 contact is consistent with the known regulation of E1alpha by PDK-family kinases, but "protein binding" itself is uninformative. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for PDHA1. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:29568061 comprehensive mapping of protein interactions and subcellular localizations |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IntAct IPI (interactor PDHB/P11177) from a proteome-scale interactome study (BioPlex). Bare "protein binding"; the PDHB interaction is captured by complex membership. Reason: Bare protein binding from a proteome-scale interaction screen is uninformative as a molecular function, and the screen supports no more specific activity for PDHA1. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome |
| GO:0005515 protein binding | IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy... | REMOVE | Summary: IntAct IPI (interactor CFTR/P13569) from a mammalian membrane two-hybrid CFTR-interactome screen. A CFTR-PDHA1 contact from a high-throughput screen is of uncertain physiological relevance and the term is uninformative. Reason: Bare protein binding from a targeted CFTR-interactome screen (mammalian membrane two-hybrid) is uninformative as a molecular function. A contact between the plasma-membrane channel CFTR and the mitochondrial-matrix PDHA1 is of uncertain physiological relevance, and the screen supports no more specific activity for PDHA1. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hybrid |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | REMOVE | Summary: IntAct IPI (interactor CFTR/P13569) from a differential CFTR proximity-labeling study. As above, high-throughput CFTR-proximity evidence; uninformative MF term. Reason: Bare protein binding from a targeted CFTR-interactome proximity-labeling study is uninformative as a molecular function. Proximity labeling reports nearness, not direct binding, and a CFTR-PDHA1 proximity hit is of uncertain physiological relevance; the study supports no more specific activity for PDHA1. Removal does not mean the reported interaction is false. Supporting Evidence: PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures |
| GO:0005515 protein binding | IPI PMID:7782287 Mutagenesis studies of the phosphorylation sites of recombin... | REMOVE | Summary: IntAct IPI (interactor PDK1/Q15118) linked to the mutagenesis study of the E1alpha phosphorylation sites. Reflects the physiologically important E1alpha-PDK interaction (PDK phosphorylates and inactivates E1), but the bare "protein binding" term is uninformative. Reason: Bare protein binding is uninformative. PDHA1 is the substrate in this interaction (PDK phosphorylates the E1alpha regulatory serines); the enzyme-substrate relationship belongs on the enzyme, and no more specific molecular function of PDHA1 is supported. Removal does not mean the interaction is false. Supporting Evidence: PMID:7782287 regulated by phosphorylation-dephosphorylation, catalyzed by the E1-kinase |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated (IEA) mitochondrion localization. Correct but less specific than the mitochondrial matrix annotations. Reason: Correct compartment; parent of the more specific matrix location that better represents PDHA1. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MODIFY | Summary: Automated (Ensembl Compara) generic protein-containing complex membership. This is uninformative given that the specific complex (pyruvate dehydrogenase complex, GO:0045254) is already annotated. Reason: Too general; PDHA1's complex is specifically the pyruvate dehydrogenase complex. Proposed replacements: pyruvate dehydrogenase complex Supporting Evidence: PMID:19240034 pyruvate dehydrogenase (E1p) |
| GO:0005739 mitochondrion | NAS PMID:24534072 Component co-expression and purification of recombinant huma... | KEEP AS NON CORE | Summary: Non-traceable-author-statement mitochondrion localization from ComplexPortal, based on the PDC being a mitochondrial enzyme. Correct but less specific than matrix. Reason: Correct compartment (the mammalian PDC is a mitochondrial enzyme); matrix is the more precise location. Supporting Evidence: PMID:24534072 The mammalian pyruvate dehydrogenase complex (PDC) is a multi-component mitochondrial enzyme |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IDA PMID:19081061 Structural basis for inactivation of the human pyruvate dehy... | ACCEPT | Summary: Direct experimental (IDA) annotation from the human E1p structure/kinetics study showing PDHA1's role in converting pyruvate to acetyl-CoA within the PDH complex. Reason: Strong experimental support for the core process; the study measures the overall PDC reaction and E1p decarboxylation/reductive acetylation activities. Supporting Evidence: PMID:19081061 catalyzes the oxidative decarboxylation of pyruvate to produce acetyl-CoA and NADH |
| GO:0006086 pyruvate decarboxylation to acetyl-CoA | IDA PMID:24534072 Component co-expression and purification of recombinant huma... | ACCEPT | Summary: Direct experimental (IDA) annotation from the recombinant human PDC that produced a functional, active complex, confirming PDHA1's role in the pyruvate-to-acetyl-CoA process. Reason: Functional reconstituted PDC demonstrates the process; supports the core role. Supporting Evidence: PMID:24534072 conversion of pyruvate to acetyl-CoA connecting glycolysis to the citric acid cycle |
| GO:0045254 pyruvate dehydrogenase complex | IDA PMID:19081061 Structural basis for inactivation of the human pyruvate dehy... | ACCEPT | Summary: Direct experimental complex-membership annotation for PDHA1 as the E1 alpha subunit of the PDC, from the human E1p structural study. Reason: PDHA1 is experimentally established as part of the PDH complex (E1 heterotetramer). Supporting Evidence: PMID:19081061 Phosphorylation of the heterotetrameric (Ξ±2Ξ²2) E1p component |
| GO:0045254 pyruvate dehydrogenase complex | IPI PMID:19240034 Subunit and catalytic component stoichiometries of an in vit... | ACCEPT | Summary: ComplexPortal IPI complex-membership annotation from the study defining the subunit stoichiometry of the reconstituted human PDC, in which PDHA1 (as E1p heterotetramer) associates with the E2p/E3BP core. Reason: Establishes PDHA1 as part of the assembled PDH complex. Supporting Evidence: PMID:19240034 40 copies of E1p heterotetramers and 20 copies of E3 dimers associated with the E2p/E3BP core |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Immunofluorescence-based (Human Protein Atlas) mitochondrion localization. Correct compartment; less specific than matrix. Reason: Consistent mitochondrial localization; matrix is the more precise sub-compartment. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0004739 pyruvate dehydrogenase (acetyl-transferring) activity | EXP PMID:17474719 Phosphorylation of serine 264 impedes active site accessibil... | ACCEPT | Summary: Direct experimental (EXP) annotation of pyruvate dehydrogenase activity based on kinetic characterization of human E1 (wild-type and S264-phosphorylation variant), demonstrating pyruvate decarboxylation and reductive acetylation of E2. Reason: This is the strongest, most direct experimental evidence for the core molecular function of PDHA1. Supporting Evidence: PMID:17474719 the pyruvate dehydrogenase multienzyme complex (PDHc) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA |
| GO:0004739 pyruvate dehydrogenase (acetyl-transferring) activity | EXP PMID:7782287 Mutagenesis studies of the phosphorylation sites of recombin... | ACCEPT | Summary: Direct experimental (EXP) annotation of pyruvate dehydrogenase activity from site-directed mutagenesis of recombinant human E1 phosphorylation sites, measuring E1 specific activity and Km for TPP and pyruvate. Reason: Experimental measurement of E1 catalytic activity on the human protein supports the core molecular function. Supporting Evidence: PMID:7782287 Mutation at site 1 but not at sites 2 and/or 3 decreased E1 specific activity and also increased Km values for thiamin pyrophosphate and pyruvate |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based (ISS) transfer of the mitochondrial matrix location from an ortholog. Consistent with the curated matrix location. Reason: Correct compartment for PDHA1, matching UniProt and the IBA annotation. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity-based (ISS) transfer of mitochondrion (is_active_in) from an ortholog. Correct but less specific than matrix. Reason: Correct compartment; matrix is the more precise location where PDHA1 is active. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput proteomics (HTP) mitochondrion localization from a quantitative high-confidence human mitochondrial proteome (MitoCoP). Supports mitochondrial residence; less specific than matrix. Reason: Consistent with mitochondrial localization; parent of the matrix location. Supporting Evidence: PMID:34800366 mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP) |
| GO:0004739 pyruvate dehydrogenase (acetyl-transferring) activity | IDA PMID:19081061 Structural basis for inactivation of the human pyruvate dehy... | ACCEPT | Summary: Direct experimental (IDA) annotation with the contributes_to qualifier: PDHA1 contributes the E1 catalytic activity to the pyruvate dehydrogenase activity of the multi-subunit complex. The contributes_to qualifier is appropriate because the full activity requires the heterotetramer and the assembled PDC. Reason: Correct use of contributes_to for a subunit whose activity is realized in the context of the E1 heterotetramer / PDH complex. Supporting Evidence: PMID:19081061 The E1p component catalyzes the ThDP-mediated decarboxylation of pyruvate |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-203946 | ACCEPT | Summary: Reactome TAS matrix localization associated with the PDK phosphorylation reaction of the PDHC E1 subunit. Correct compartment. Reason: Reactome places the PDH E1 subunit and its phospho-regulation in the mitochondrial matrix, consistent with all other evidence. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-204169 | ACCEPT | Summary: Reactome TAS matrix localization associated with the PDP1/2 dephosphorylation reaction of phospho-lipo-PDH. Correct compartment. Reason: Consistent matrix localization for the reversibly phospho-regulated PDH E1 subunit. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838035 | ACCEPT | Summary: Reactome TAS matrix localization associated with the CLPXP protease binding mitochondrial matrix proteins reaction (PDHA1 as a matrix substrate). Location correct. Reason: PDHA1 is a mitochondrial matrix protein; the annotation reflects its residence in the matrix (here as a CLPXP substrate). Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9838289 | ACCEPT | Summary: Reactome TAS matrix localization associated with the CLPXP degradation of mitochondrial matrix proteins reaction. Location correct. Reason: Reflects PDHA1's matrix residence (as a substrate of matrix quality-control proteolysis); the location is correct. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9861616 | ACCEPT | Summary: Reactome TAS matrix localization associated with the DLD (E3) dihydrolipoyl dehydrogenation reaction of the PDC. Correct compartment for the PDC. Reason: The PDH complex, including PDHA1, operates in the mitochondrial matrix. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9861667 | ACCEPT | Summary: Reactome TAS matrix localization associated with the DLAT (E2) acetyl transfer to CoA reaction of the PDC. Correct compartment. Reason: The PDC reaction sequence, of which PDHA1 is the E1 component, takes place in the matrix. Supporting Evidence: file:human/PDHA1/PDHA1-uniprot.txt Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9861734 | ACCEPT | Summary: Reactome TAS matrix localization associated with the reaction in which PDH E1 decarboxylates pyruvate and transfers acetyl to DLAT. This is PDHA1's own catalytic step and it is placed in the mitochondrial matrix. Reason: Directly describes PDHA1's E1 catalytic reaction occurring in the mitochondrial matrix. Supporting Evidence: Reactome:R-HSA-9861734 The E1 component of the pyruvate dehydrogenase complex (PDC, PDHC) catalyzes the decarboxylation of pyruvate (PYR) with subsequent transfer of acetyl to the E2 subunit (DLAT) |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | MARK AS OVER ANNOTATED | Summary: High-throughput proteomic detection of PDHA1 in an isolated human sperm nucleus preparation. This does not establish a nuclear function or a physiological nuclear localization for the somatic E1alpha, which is an established mitochondrial matrix protein; it likely reflects the specialized sperm proteome and/or preparation carry-over. Reason: Single high-throughput proteomic dataset in a specialized cell type; not corroborated as a functional nuclear localization. The compartment of any non-mitochondrial pool is unresolved. Retained (experimental HDA) but flagged as over-annotation, not core. Supporting Evidence: PMID:21630459 sperm nuclei were obtained |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of PDHA1 in mitochondria isolated from human skeletal muscle (a mitochondrial phosphoproteome). Supports mitochondrial residence; less specific than matrix. Reason: Consistent mitochondrial localization; parent of the matrix location. Supporting Evidence: PMID:20833797 mitochondria isolated from resting human muscle |
| GO:0005739 mitochondrion | TAS PMID:3034892 The human pyruvate dehydrogenase complex. Isolation of cDNA ... | KEEP AS NON CORE | Summary: Traceable-author-statement mitochondrion localization from the original human E1alpha cDNA characterization, which established the mitochondrial import leader and matrix maturation of the protein. Reason: Correct compartment; the same study establishes mitochondrial import, and matrix is the precise location. Supporting Evidence: PMID:3034892 The protein is synthesized with a typical mitochondrial import leader |
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