id: P08559
gene_symbol: PDHA1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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).
alternative_products:
- name: '1'
  id: P08559-1
- name: '2'
  id: P08559-2
  sequence_note: VSP_042569
- name: '3'
  id: P08559-3
  sequence_note: VSP_042570
- name: '4'
  id: P08559-4
  sequence_note: VSP_043363
existing_annotations:
- term:
    id: GO:0004739
    label: pyruvate dehydrogenase (acetyl-transferring) activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct and central function. E1alpha, with E1beta, catalyzes the TPP-dependent
      decarboxylation of pyruvate and reductive acetylation of the E2 lipoyl group.
    supported_by:
    - reference_id: PMID:19081061
      supporting_text: >-
        The E1p component catalyzes the ThDP-mediated decarboxylation of pyruvate
        (Reaction 2) and the reductive acetylation of a lipoyl group
    - reference_id: PMID:3034892
      supporting_text: >-
        the alpha subunit of
        human pyruvate dehydrogenase (EC 1.2.4.1), the E1 component of the pyruvate
        dehydrogenase complex
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    reason: >-
      PDHA1 is synthesized with a mitochondrial import leader and functions in the
      matrix as part of the soluble PDH complex.
    supported_by:
    - reference_id: PMID:3034892
      supporting_text: >-
        The protein is synthesized with a typical mitochondrial import leader
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      This is the core process to which the E1 catalytic activity contributes; the
      PDH complex converts pyruvate to acetyl-CoA and CO2.
    supported_by:
    - reference_id: PMID:19081061
      supporting_text: >-
        The human pyruvate dehydrogenase complex (PDC) catalyzes the oxidative
        decarboxylation of pyruvate to produce acetyl-CoA and NADH
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    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).
    action: ACCEPT
    reason: >-
      PDHA1 forms the E1 heterotetramer with PDHB and is a core component of the
      multienzyme PDH complex.
    supported_by:
    - reference_id: PMID:19240034
      supporting_text: >-
        The human pyruvate dehydrogenase complex (PDC) is a 9.5-megadalton
        catalytic
        machine that employs three catalytic components, i.e. pyruvate dehydrogenase
        (E1p)
- term:
    id: GO:0004739
    label: pyruvate dehydrogenase (acetyl-transferring) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Correctly captures the enzymatic function via EC/RHEA/InterPro mapping.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "EC=1.2.4.1"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Automated location annotation derived from the UniProt subcellular location
      controlled vocabulary (mitochondrion matrix, SL-0170).
    action: ACCEPT
    reason: >-
      Consistent with the curated UniProt subcellular location and the IBA
      matrix annotation.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct process for the E1 subunit of the PDH complex.
    supported_by:
    - reference_id: PMID:19081061
      supporting_text: >-
        catalyzes the oxidative decarboxylation of pyruvate to produce acetyl-CoA
- term:
    id: GO:0016624
    label: oxidoreductase activity, acting on the aldehyde or oxo group of donors,
      disulfide as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0004739
      label: pyruvate dehydrogenase (acetyl-transferring) activity
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "EC=1.2.4.1"
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: >-
      Automated (ARBA) assertion that PDHA1 is part of the pyruvate dehydrogenase
      complex. Redundant with IBA/IDA complex annotations.
    action: ACCEPT
    reason: >-
      Correct complex assignment for the E1 alpha subunit.
    supported_by:
    - reference_id: PMID:19240034
      supporting_text: >-
        pyruvate dehydrogenase
        (E1p)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12651851
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real experimental interaction (E1alpha-E1beta), but GO:0005515 conveys no
      specific function; retain as non-core evidence rather than a core annotation.
      Per curation policy, an experimental IPI is not removed.
    supported_by:
    - reference_id: PMID:12651851
      supporting_text: >-
        In
        alpha2beta2-heterotetrameric human pyruvate dehydrogenase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29128334
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput interaction evidence; the informative content (PDH complex
      membership) is captured elsewhere. Not removed per policy for experimental IPI.
    supported_by:
    - reference_id: PMID:29128334
      supporting_text: A Map of Human Mitochondrial Protein Interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29568061
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Proximity/AP-MS-derived interaction; biologically the regulatory PDK contact,
      but a bare protein-binding term is not a useful function annotation.
    supported_by:
    - reference_id: PMID:29568061
      supporting_text: comprehensive mapping of protein
        interactions and subcellular localizations
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IntAct IPI (interactor PDHB/P11177) from a proteome-scale interactome study
      (BioPlex). Bare "protein binding"; the PDHB interaction is captured by complex
      membership.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Large-scale interactome evidence; uninformative MF term. Not removed per policy.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
        of the human
        interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35156780
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput screen against CFTR; bare protein-binding term with no clear
      functional meaning for PDHA1. Not removed (experimental IPI).
    supported_by:
    - reference_id: PMID:35156780
      supporting_text: CFTR interactome mapping using the mammalian membrane two-hybrid
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36012204
  qualifier: enables
  review:
    summary: >-
      IntAct IPI (interactor CFTR/P13569) from a differential CFTR proximity-labeling
      study. As above, high-throughput CFTR-proximity evidence; uninformative MF term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Proximity-labeling screen; not a core PDHA1 function and the term is
      uninformative. Not removed per policy.
    supported_by:
    - reference_id: PMID:36012204
      supporting_text: Differential CFTR-Interactome Proximity Labeling Procedures
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7782287
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real regulatory interaction (E1alpha is the PDK substrate), but captured better
      as regulation/phosphorylation than as generic protein binding.
    supported_by:
    - reference_id: PMID:7782287
      supporting_text: >-
        regulated by
        phosphorylation-dephosphorylation, catalyzed by the E1-kinase
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Automated (IEA) mitochondrion localization. Correct but less specific than the
      mitochondrial matrix annotations.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; parent of the more specific matrix location that better
      represents PDHA1.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    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.
    action: MODIFY
    reason: >-
      Too general; PDHA1's complex is specifically the pyruvate dehydrogenase complex.
    proposed_replacement_terms:
    - id: GO:0045254
      label: pyruvate dehydrogenase complex
    supported_by:
    - reference_id: PMID:19240034
      supporting_text: >-
        pyruvate dehydrogenase
        (E1p)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:24534072
  qualifier: located_in
  review:
    summary: >-
      Non-traceable-author-statement mitochondrion localization from ComplexPortal,
      based on the PDC being a mitochondrial enzyme. Correct but less specific than
      matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment (the mammalian PDC is a mitochondrial enzyme); matrix is
      the more precise location.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: >-
        The mammalian pyruvate dehydrogenase complex (PDC) is a multi-component
        mitochondrial enzyme
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IDA
  original_reference_id: PMID:19081061
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Strong experimental support for the core process; the study measures the overall
      PDC reaction and E1p decarboxylation/reductive acetylation activities.
    supported_by:
    - reference_id: PMID:19081061
      supporting_text: >-
        catalyzes the oxidative decarboxylation of pyruvate to produce acetyl-CoA
        and NADH
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IDA
  original_reference_id: PMID:24534072
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Functional reconstituted PDC demonstrates the process; supports the core role.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: >-
        conversion of pyruvate to
        acetyl-CoA connecting glycolysis to the citric acid cycle
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:19081061
  qualifier: part_of
  review:
    summary: >-
      Direct experimental complex-membership annotation for PDHA1 as the E1 alpha
      subunit of the PDC, from the human E1p structural study.
    action: ACCEPT
    reason: >-
      PDHA1 is experimentally established as part of the PDH complex (E1 heterotetramer).
    supported_by:
    - reference_id: PMID:19081061
      supporting_text: >-
        Phosphorylation of the heterotetrameric (α2β2) E1p component
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IPI
  original_reference_id: PMID:19240034
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    reason: >-
      Establishes PDHA1 as part of the assembled PDH complex.
    supported_by:
    - reference_id: PMID:19240034
      supporting_text: >-
        40
        copies of E1p heterotetramers and 20 copies of E3 dimers associated with the
        E2p/E3BP core
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (Human Protein Atlas) mitochondrion localization.
      Correct compartment; less specific than matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent mitochondrial localization; matrix is the more precise sub-compartment.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0004739
    label: pyruvate dehydrogenase (acetyl-transferring) activity
  evidence_type: EXP
  original_reference_id: PMID:17474719
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      This is the strongest, most direct experimental evidence for the core molecular
      function of PDHA1.
    supported_by:
    - reference_id: PMID:17474719
      supporting_text: >-
        the
        pyruvate dehydrogenase multienzyme complex (PDHc) catalyzes the oxidative
        decarboxylation of pyruvate to acetyl-CoA
- term:
    id: GO:0004739
    label: pyruvate dehydrogenase (acetyl-transferring) activity
  evidence_type: EXP
  original_reference_id: PMID:7782287
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Experimental measurement of E1 catalytic activity on the human protein supports
      the core molecular function.
    supported_by:
    - reference_id: PMID:7782287
      supporting_text: >-
        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
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity-based (ISS) transfer of the mitochondrial matrix location
      from an ortholog. Consistent with the curated matrix location.
    action: ACCEPT
    reason: >-
      Correct compartment for PDHA1, matching UniProt and the IBA annotation.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: is_active_in
  review:
    summary: >-
      Sequence-similarity-based (ISS) transfer of mitochondrion (is_active_in) from an
      ortholog. Correct but less specific than matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; matrix is the more precise location where PDHA1 is active.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics (HTP) mitochondrion localization from a quantitative
      high-confidence human mitochondrial proteome (MitoCoP). Supports mitochondrial
      residence; less specific than matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with mitochondrial localization; parent of the matrix location.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
- term:
    id: GO:0004739
    label: pyruvate dehydrogenase (acetyl-transferring) activity
  evidence_type: IDA
  original_reference_id: PMID:19081061
  qualifier: contributes_to
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct use of contributes_to for a subunit whose activity is realized in the
      context of the E1 heterotetramer / PDH complex.
    supported_by:
    - reference_id: PMID:19081061
      supporting_text: >-
        The E1p component catalyzes the ThDP-mediated decarboxylation of pyruvate
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-203946
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with the PDK phosphorylation reaction
      of the PDHC E1 subunit. Correct compartment.
    action: ACCEPT
    reason: >-
      Reactome places the PDH E1 subunit and its phospho-regulation in the mitochondrial
      matrix, consistent with all other evidence.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-204169
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with the PDP1/2 dephosphorylation
      reaction of phospho-lipo-PDH. Correct compartment.
    action: ACCEPT
    reason: >-
      Consistent matrix localization for the reversibly phospho-regulated PDH E1 subunit.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838035
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with the CLPXP protease binding
      mitochondrial matrix proteins reaction (PDHA1 as a matrix substrate). Location
      correct.
    action: ACCEPT
    reason: >-
      PDHA1 is a mitochondrial matrix protein; the annotation reflects its residence in
      the matrix (here as a CLPXP substrate).
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838289
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with the CLPXP degradation of
      mitochondrial matrix proteins reaction. Location correct.
    action: ACCEPT
    reason: >-
      Reflects PDHA1's matrix residence (as a substrate of matrix quality-control
      proteolysis); the location is correct.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861616
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with the DLD (E3) dihydrolipoyl
      dehydrogenation reaction of the PDC. Correct compartment for the PDC.
    action: ACCEPT
    reason: >-
      The PDH complex, including PDHA1, operates in the mitochondrial matrix.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861667
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS matrix localization associated with the DLAT (E2) acetyl transfer to
      CoA reaction of the PDC. Correct compartment.
    action: ACCEPT
    reason: >-
      The PDC reaction sequence, of which PDHA1 is the E1 component, takes place in the
      matrix.
    supported_by:
    - reference_id: file:human/PDHA1/PDHA1-uniprot.txt
      supporting_text: "Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861734
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Directly describes PDHA1's E1 catalytic reaction occurring in the mitochondrial
      matrix.
    supported_by:
    - reference_id: Reactome:R-HSA-9861734
      supporting_text: >-
        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)
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21630459
      supporting_text: >-
        sperm nuclei were obtained
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:20833797
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomic detection of PDHA1 in mitochondria isolated from human
      skeletal muscle (a mitochondrial phosphoproteome). Supports mitochondrial
      residence; less specific than matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent mitochondrial localization; parent of the matrix location.
    supported_by:
    - reference_id: PMID:20833797
      supporting_text: >-
        mitochondria isolated from resting human
        muscle
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:3034892
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; the same study establishes mitochondrial import, and matrix
      is the precise location.
    supported_by:
    - reference_id: PMID:3034892
      supporting_text: >-
        The protein is synthesized with a typical mitochondrial import leader
core_functions:
- description: >-
    Thiamine-pyrophosphate (TPP)- and Mg2+-dependent E1 alpha subunit of the pyruvate
    dehydrogenase complex that, together with PDHB (E1beta), catalyzes the oxidative
    decarboxylation of pyruvate and the reductive acetylation of the E2 lipoyl group,
    the committed step converting pyruvate to acetyl-CoA and linking glycolysis to the
    TCA cycle.
  molecular_function:
    id: GO:0004739
    label: pyruvate dehydrogenase (acetyl-transferring) activity
  directly_involved_in:
  - id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  in_complex:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  supported_by:
  - reference_id: PMID:19081061
    supporting_text: >-
      The E1p component catalyzes the ThDP-mediated decarboxylation of pyruvate
      (Reaction 2) and the reductive acetylation of a lipoyl group
  - reference_id: PMID:17474719
    supporting_text: >-
      the
      pyruvate dehydrogenase multienzyme complex (PDHc) catalyzes the oxidative
      decarboxylation of pyruvate to acetyl-CoA
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12651851
  title: Structural basis for flip-flop action of thiamin pyrophosphate-dependent
    enzymes revealed by human pyruvate dehydrogenase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structure of holo human E1 (alpha2beta2) with Mg2+ and TPP; establishes
      the TPP/Mg2+ cofactor site and the alpha-beta heterotetramer. Interaction PMID for
      the PDHA1-PDHB IntAct entry.
- id: PMID:17474719
  title: Phosphorylation of serine 264 impedes active site accessibility in the E1
    component of the human pyruvate dehydrogenase multienzyme complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Kinetic + structural study of human E1 and the S264 phospho-variant; supports the
      EXP pyruvate dehydrogenase activity annotation and phospho-regulation.
- id: PMID:19081061
  title: 'Structural basis for inactivation of the human pyruvate dehydrogenase complex
    by phosphorylation: role of disordered phosphorylation loops.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; defines the E1p reactions, PDC overall reaction, matrix
      context, phosphorylation sites, and Km for pyruvate. Primary support for MF/BP/CC
      core annotations.
- id: PMID:19240034
  title: Subunit and catalytic component stoichiometries of an in vitro reconstituted
    human pyruvate dehydrogenase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reconstituted human PDC stoichiometry; supports PDHA1 (E1p heterotetramer) as part
      of the assembled complex.
- id: PMID:20833797
  title: Phosphoproteome analysis of functional mitochondria isolated from resting
    human muscle reveals extensive phosphorylation of inner membrane protein complexes
    and enzymes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Mitochondrial phosphoproteome of human muscle; supports mitochondrial localization
      (HDA) but is high-throughput.
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Sperm-nucleus proteome; the PDHA1 nucleus HDA is a single high-throughput
      detection in a specialized cell type and does not establish a physiological nuclear
      function for the mitochondrial matrix enzyme.
- id: PMID:24534072
  title: Component co-expression and purification of recombinant human pyruvate dehydrogenase
    complex from baculovirus infected SF9 cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Functional recombinant human PDC; supports the pyruvate-to-acetyl-CoA process and
      mitochondrial-enzyme identity.
- id: PMID:29128334
  title: A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration
    Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale mitochondrial interactome; PDHA1 interactions (PDHB, IMMT) are
      high-throughput and captured better as complex membership than as protein binding.
- id: PMID:29568061
  title: An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein
    interactions and subcellular localizations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      AP-MS/BioID methods paper; PDHA1-PDK1 IntAct entry; high-throughput evidence for a
      known regulatory contact.
- id: PMID:3034892
  title: The human pyruvate dehydrogenase complex. Isolation of cDNA clones for the
    E1 alpha subunit, sequence analysis, and characterization of the mRNA.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original human E1alpha cDNA/protein characterization; establishes EC 1.2.4.1
      identity and mitochondrial import leader / matrix maturation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale interactome (BioPlex); PDHA1-PDHB IntAct entry; high-throughput.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      MitoCoP high-confidence mitochondrial proteome; supports mitochondrial
      localization (HTP).
- id: PMID:35156780
  title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput
    screening system.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Membrane two-hybrid CFTR screen; PDHA1-CFTR contact of uncertain physiological
      relevance; uninformative protein-binding annotation.
- id: PMID:36012204
  title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment
    in Multiple SLC Transporters.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      CFTR proximity-labeling study; PDHA1-CFTR contact; high-throughput, uninformative
      MF term.
- id: PMID:7782287
  title: Mutagenesis studies of the phosphorylation sites of recombinant human pyruvate
    dehydrogenase. Site-specific regulation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Mutagenesis of E1alpha phosphorylation sites; supports EXP pyruvate dehydrogenase
      activity and phospho-regulation; also the PDHA1-PDK1 IntAct entry.
- id: Reactome:R-HSA-203946
  title: PDK isozymes phosphorylate PDHC subunit E1
  findings: []
- id: Reactome:R-HSA-204169
  title: PDP1,2 dephosphorylate p-lipo-PDH
  findings: []
- id: Reactome:R-HSA-9838035
  title: CLPXP binds mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838289
  title: CLPXP degrades mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9861616
  title: DLD dimer dehydrogenates dihydrolipoyl
  findings: []
- id: Reactome:R-HSA-9861667
  title: DLAT trimer transfers acetyl to CoA
  findings: []
- id: Reactome:R-HSA-9861734
  title: PDH E1 decarboxylates PYR, transferring acetyl to DLAT
  findings: []