id: P10515
gene_symbol: DLAT
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DLAT is the dihydrolipoyllysine-residue acetyltransferase (E2) component
  of the mitochondrial pyruvate dehydrogenase complex (PDC), EC 2.3.1.12. It carries
  covalently bound lipoyl cofactors on two lipoyl-binding domains (Lys132 and Lys259)
  and catalyzes the second step of the overall pyruvate-to-acetyl-CoA reaction, accepting
  the acetyl group from the acetyl-dihydrolipoyl intermediate generated by the E1
  component and transferring it to coenzyme A to form acetyl-CoA. The C-terminal catalytic
  (inner) domains of E2, together with the E3-binding protein (PDHX), assemble into
  a 60-meric dodecahedral core with icosahedral symmetry that forms the structural
  scaffold of the PDC and to which the peripheral E1 and E3 enzymes and the regulatory
  kinases (PDK) and phosphatases (PDP) attach. Acting in the mitochondrial matrix,
  the PDC links cytosolic glycolysis to the tricarboxylic acid cycle by supplying
  acetyl-CoA. Biallelic loss-of-function variants in DLAT cause pyruvate dehydrogenase
  E2 deficiency, a rare subtype of PDC deficiency presenting with lactic acidosis,
  episodic dystonia and neurologic dysfunction. DLAT is also the 70-kDa M2 mitochondrial
  autoantigen recognized by antimitochondrial antibodies in primary biliary cholangitis.
existing_annotations:
- term:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of the E2 acetyltransferase activity, the
      defining catalytic function of DLAT. Well supported by direct experimental data
      in human and orthologs.
    action: ACCEPT
    reason: This is the core, defining molecular function of DLAT (EC 2.3.1.12) and
      is corroborated by IDA evidence in the same GOA set.
    supported_by:
    - reference_id: PMID:20160912
      supporting_text: E2 then transfers the acetyl moiety to CoA forming acetyl-CoA.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of mitochondrial localization. Correct but the
      more specific matrix term (GO:0005759) better captures where DLAT acts.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrion is a correct but general compartment; the mitochondrial
      matrix annotations are more informative for the core function.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION 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 assignment of the overall PDC process to which DLAT contributes
      the E2 acetyltransfer step. This is the core biological process for DLAT.
    action: ACCEPT
    reason: DLAT catalyzes the E2 step of the pyruvate-to-acetyl-CoA conversion; this
      is its core process and is supported by multiple experimental annotations.
    supported_by:
    - reference_id: PMID:20160912
      supporting_text: E2 then transfers the acetyl moiety to CoA forming acetyl-CoA.
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment of DLAT as part of the PDC. DLAT (E2) forms the
      structural core of this complex.
    action: ACCEPT
    reason: DLAT is the E2 core subunit of the PDC; this complex membership is central
      to its function and confirmed experimentally.
    supported_by:
    - reference_id: PMID:19240034
      supporting_text: The human PDC is organized around a 60-meric
- term:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (ARBA/InterPro/EC 2.3.1.12/RHEA:17017) assignment of the core
      E2 acetyltransferase activity. Consistent with the experimental annotations.
    action: ACCEPT
    reason: Correctly maps the EC 2.3.1.12 catalytic activity that is DLAT's core
      function; the UniProt record carries the same EC/RHEA reaction.
    supported_by:
    - reference_id: PMID:20160912
      supporting_text: E2 then transfers the acetyl moiety to CoA forming acetyl-CoA.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of mitochondrial matrix localization (UniProtKB-SubCell
      SL-0170). This is the compartment where DLAT and the PDC act.
    action: ACCEPT
    reason: Matrix localization is the correct, specific compartment for DLAT and
      is stated in the UniProt SUBCELLULAR LOCATION field.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION 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: Electronic assignment of the core PDC process. Consistent with experimental
      annotations to the same term.
    action: ACCEPT
    reason: Correct core process; duplicate of experimentally supported annotations.
    supported_by:
    - reference_id: PMID:20160912
      supporting_text: E2 then transfers the acetyl moiety to CoA forming acetyl-CoA.
- term:
    id: GO:0016746
    label: acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO electronic assignment of the general acyltransferase parent
      term. Correct but far less specific than GO:0004742.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a general parent of the specific dihydrolipoyllysine-residue acetyltransferase
      activity that DLAT enables; retained but not core, as the specific term is annotated.
    supported_by:
    - reference_id: PMID:9045657
      supporting_text: Purified E2 had a high
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Electronic assignment of PDC membership. Consistent with experimental
      complex annotations.
    action: ACCEPT
    reason: Correct core complex membership; duplicate of experimentally supported
      annotations.
    supported_by:
    - reference_id: PMID:19240034
      supporting_text: The human PDC is organized around a 60-meric
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17683942
  qualifier: enables
  review:
    summary: IntAct IPI capturing the DLAT(E2)-PDK3 interaction (lipoyl domain 2 in
      complex with pyruvate dehydrogenase kinase 3). A real, structurally characterized
      interaction, but the term itself is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" conveys no specific function. The underlying interaction
      (DLAT lipoyl domain 2 with PDK3) is genuine and relates to PDC regulation, but
      per curation policy this term is marked as over-annotated rather than removed.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: Interacts with PDK2 and PDK3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18206651
  qualifier: enables
  review:
    summary: IntAct IPI capturing the DLAT(E2)-PDHB (E1 beta) interaction. The E1
      component binds the subunit-binding domain of E2. Real interaction, uninformative
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative; the specific E1-E2 assembly interaction
      is real but is better captured by complex membership. Marked over-annotated
      per policy rather than removed.
    supported_by:
    - reference_id: PMID:18206651
      supporting_text: (E1) is bound to the E1-binding domain of dihydrolipoamide
        acetyltransferase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25525879
  qualifier: enables
  review:
    summary: IntAct IPI capturing the DLAT-SIRT4 interaction. SIRT4 is a lipoamidase
      that delipoylates DLAT to regulate PDC activity. Real interaction, uninformative
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative. The DLAT-SIRT4 interaction is
      genuine and regulatory, but the term is marked over-annotated per policy.
    supported_by:
    - reference_id: PMID:25525879
      supporting_text: SIRT4 hydrolyzes lipoamide cofactors from the DLAT E2 component
        of the PDH complex, thereby inhibiting PDH activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput affinity-capture interactome (BioPlex) IPI to PDK3. Real
      but uninformative bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" from a proteome-scale interactome; uninformative
      as a molecular function. Marked over-annotated per policy.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: Interacts with PDK2 and PDK3
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput proteome-scale interactome (BioPlex 3.0) IPI (PDHB/PDK3).
      Real but uninformative bare protein-binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" from a large interactome study; uninformative as
      a molecular function. Marked over-annotated per policy.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: Interacts with PDHB
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18184587
  qualifier: enables
  review:
    summary: IPI for DLAT self-association. E2 self-assembles into the 60-meric central
      core of the PDC, so identical protein binding (homo-oligomerization) is a genuine
      and informative structural property.
    action: KEEP_AS_NON_CORE
    reason: DLAT self-assembles into the dodecahedral E2 core; identical protein binding
      captures this real structural oligomerization. Kept as a supporting structural
      annotation, non-core relative to the catalytic activity.
    supported_by:
    - reference_id: PMID:18184587
      supporting_text: consisting of a central E2 core decorated by a shell of peripheral
        enzymes
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18184588
  qualifier: enables
  review:
    summary: IPI for DLAT self-association based on cryo-EM of the human E2 core. E2
      trimers assemble into the 60-meric dodecahedral inner core.
    action: KEEP_AS_NON_CORE
    reason: Captures the genuine homo-oligomeric self-assembly of E2 into the PDC
      core. Kept as a supporting structural annotation, non-core relative to catalysis.
    supported_by:
    - reference_id: PMID:18184588
      supporting_text: Dihydrolipoyl acetyltransferase (E2) is the central component
        of pyruvate
- term:
    id: GO:0016407
    label: acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ensembl-projected (from mouse ortholog) electronic assignment of the
      general acetyltransferase parent term. Correct but less specific than GO:0004742.
    action: MARK_AS_OVER_ANNOTATED
    reason: General parent of the specific dihydrolipoyllysine-residue acetyltransferase
      activity; retained but not core because the specific term is annotated.
    supported_by:
    - reference_id: PMID:9045657
      supporting_text: Purified E2 had a high
- term:
    id: GO:0042867
    label: pyruvate catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected electronic assignment of the general pyruvate catabolism
      process. Correct but broader than the specific pyruvate-to-acetyl-CoA process.
    action: KEEP_AS_NON_CORE
    reason: A correct but more general process term; the specific pyruvate decarboxylation
      to acetyl-CoA (GO:0006086) is the core process annotation.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: plays a key role in the conversion of pyruvate to
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861559
  qualifier: involved_in
  review:
    summary: Reactome TAS for the overall PDC reaction that synthesizes acetyl-CoA
      from pyruvate. Core process for DLAT as the E2 component.
    action: ACCEPT
    reason: Correct core process, curated by Reactome and consistent with experimental
      evidence.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: acetyl-CoA connecting glycolysis to the citric acid cycle
- term:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861667
  qualifier: enables
  review:
    summary: Reactome TAS for the DLAT-catalyzed transfer of the acetyl group from
      acetyllipoyl-lysine to CoA. This is the defining E2 reaction.
    action: ACCEPT
    reason: Core catalytic function, curated by Reactome (DLAT trimer transfers acetyl
      to CoA) and consistent with the EC 2.3.1.12 reaction.
    supported_by:
    - reference_id: PMID:20160912
      supporting_text: E2 then transfers the acetyl moiety to CoA forming acetyl-CoA.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:24534072
  qualifier: located_in
  review:
    summary: ComplexPortal NAS for mitochondrial localization. Correct but general
      compartment.
    action: KEEP_AS_NON_CORE
    reason: Correct but general compartment; the mitochondrial matrix term is more
      informative for the core function.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: The mammalian pyruvate dehydrogenase complex (PDC) is a
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IDA
  original_reference_id: PMID:24534072
  qualifier: involved_in
  review:
    summary: IDA from reconstituted recombinant human PDC (all five components co-expressed
      and lipoylated) demonstrating the functional pyruvate-to-acetyl-CoA reaction.
      Core process.
    action: ACCEPT
    reason: Direct experimental support for DLAT participating in the core PDC reaction
      via a functional reconstituted complex.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: plays a key role in the conversion of pyruvate to
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IPI
  original_reference_id: PMID:19240034
  qualifier: part_of
  review:
    summary: IPI from in vitro reconstitution and stoichiometry study establishing
      DLAT (E2p) as part of the 60-meric PDC core. Core complex membership.
    action: ACCEPT
    reason: Direct evidence that DLAT (E2p) is a subunit of the PDC core; this is
      central to its function.
    supported_by:
    - reference_id: PMID:19240034
      supporting_text: dihydrolipoyl transacetylase (E2p)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence IDA for mitochondrial localization. Correct but
      general compartment.
    action: KEEP_AS_NON_CORE
    reason: Correct mitochondrial localization by immunofluorescence; general compartment,
      with matrix being the more specific and informative term.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: 'GO:0005739; C:mitochondrion; IDA:HPA'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS transfer (from rat ortholog P08461) of mitochondrial matrix localization.
      Correct specific compartment where DLAT acts.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC and is consistent
      with the UniProt SUBCELLULAR LOCATION field.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION Mitochondrion matrix
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IDA
  original_reference_id: PMID:20160912
  qualifier: involved_in
  review:
    summary: IDA from reconstitution/kinetic study of the human PDC (E1, E2, E3 components)
      supporting DLAT's role in the overall pyruvate-to-acetyl-CoA reaction. Core
      process.
    action: ACCEPT
    reason: Direct experimental support for DLAT in the core PDC process via functional
      reconstitution and activity assays.
    supported_by:
    - reference_id: PMID:20160912
      supporting_text: E2 then transfers the acetyl moiety to CoA forming acetyl-CoA.
- term:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:9242632
  qualifier: enables
  review:
    summary: MGI-curated IDA for the E2 acetyltransferase activity, from a reconstitution
      study of the human PDC (E3BP/E2). Core catalytic function. The paper title foregrounds
      E3BP (protein X), but the full-text reconstitution work assays the E2 core;
      defer to curator.
    action: ACCEPT
    reason: Direct experimental support for the defining E2 catalytic activity; consistent
      with other IDA/IEA/EC annotations to the same term.
    supported_by:
    - reference_id: PMID:9242632
      supporting_text: spontaneously reconstituted the pyruvate dehydrogenase complex
        in the presence
- term:
    id: GO:0006086
    label: pyruvate decarboxylation to acetyl-CoA
  evidence_type: IC
  original_reference_id: PMID:9242632
  qualifier: acts_upstream_of_or_within
  review:
    summary: MGI-curated IC (from the GO:0004742 activity) that DLAT acts within the
      overall pyruvate-to-acetyl-CoA process via functional PDC reconstitution. Core
      process.
    action: ACCEPT
    reason: Reasonable inference from the E2 catalytic activity to participation in
      the PDC process; consistent with the other process annotations.
    supported_by:
    - reference_id: PMID:9242632
      supporting_text: spontaneously reconstituted the pyruvate dehydrogenase complex
        in the presence
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteome study assigning DLAT to the mitochondrion.
      Correct but general compartment.
    action: KEEP_AS_NON_CORE
    reason: Correct mitochondrial localization from a high-confidence proteome; general
      compartment, with matrix being the more specific term.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-203946
  qualifier: located_in
  review:
    summary: Reactome TAS placing DLAT in the mitochondrial matrix (PDK phosphorylation
      of the PDC subunit E1 reaction). Correct specific compartment.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC; curated by Reactome.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION 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 placing DLAT in the mitochondrial matrix (PDP dephosphorylation
      reaction). Correct specific compartment.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC; curated by Reactome.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858752
  qualifier: located_in
  review:
    summary: Reactome TAS placing DLAT in the mitochondrial matrix (LIPT1 lipoyl transfer
      to DLAT reaction). Correct specific compartment.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC; curated by Reactome.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION 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 placing DLAT in the mitochondrial matrix (DLD dehydrogenation
      of dihydrolipoyl reaction). Correct specific compartment.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC; curated by Reactome.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9861626
  qualifier: located_in
  review:
    summary: Reactome TAS placing DLAT in the mitochondrial matrix (SIRT4 delipoylation
      of DLAT reaction). Correct specific compartment.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC; curated by Reactome.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION 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 placing DLAT in the mitochondrial matrix (DLAT acetyl transfer
      to CoA reaction). Correct specific compartment.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC; curated by Reactome.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION 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 placing DLAT in the mitochondrial matrix (E1 decarboxylation
      transferring acetyl to DLAT reaction). Correct specific compartment.
    action: ACCEPT
    reason: Matrix is the correct, specific compartment for DLAT/PDC; curated by Reactome.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: SUBCELLULAR LOCATION Mitochondrion matrix
- term:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:20160912
  qualifier: enables
  review:
    summary: UniProt-curated IDA for the E2 acetyltransferase activity (catalytic
      activity and interaction with PDHB reported). Core catalytic function.
    action: ACCEPT
    reason: Direct experimental support for the defining E2 catalytic activity; this
      is the source of the EC 2.3.1.12 assignment in UniProt.
    supported_by:
    - reference_id: PMID:20160912
      supporting_text: E1 carries out the decarboxylation of pyruvate and reductive
        acetylation of the lipoyl moieties of E2
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS transfer of "tricarboxylic acid cycle" involvement. DLAT/PDC feeds
      the TCA cycle by producing acetyl-CoA but the PDH reaction itself is not a step
      of the TCA cycle; this conflates an upstream feeder role with the cycle proper.
    action: MARK_AS_OVER_ANNOTATED
    reason: DLAT is not a TCA-cycle enzyme. The PDC produces acetyl-CoA that enters
      the TCA cycle, but pyruvate decarboxylation to acetyl-CoA (GO:0006086) is a
      distinct process. This ISS is an over-annotation (the correct process is annotated
      separately). Not removed outright per policy; flagged.
    supported_by:
    - reference_id: PMID:24534072
      supporting_text: acetyl-CoA connecting glycolysis to the citric acid cycle
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:9242632
  qualifier: part_of
  review:
    summary: MGI-curated IDA that DLAT (E2) is part of the reconstituted PDC. Core
      complex membership.
    action: ACCEPT
    reason: Direct experimental support for DLAT as the E2 core subunit of the PDC.
    supported_by:
    - reference_id: PMID:9242632
      supporting_text: is required for anchoring dihydrolipoamide dehydrogenase (E3)
        to the
- term:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:9045657
  qualifier: enables
  review:
    summary: MGI-curated IDA for the E2 acetyltransferase activity from recombinant,
      fully functional human E2 that assembled into the dodecahedral core and had
      high acetyltransferase activity. Core catalytic function.
    action: ACCEPT
    reason: Direct experimental demonstration of DLAT's E2 acetyltransferase activity
      using purified, assembled recombinant human protein.
    supported_by:
    - reference_id: PMID:9045657
      supporting_text: Purified E2 had a high
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:25525879
  qualifier: part_of
  review:
    summary: UniProt-curated IDA (from the SIRT4/PDH study) that DLAT is the E2 component
      of the PDC. Core complex membership.
    action: ACCEPT
    reason: Direct experimental support for DLAT as the E2 subunit forming the PDC
      catalytic core.
    supported_by:
    - reference_id: PMID:25525879
      supporting_text: DLAT also has a structural role, constituting the PDH catalytic
        core
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:20833797
  qualifier: located_in
  review:
    summary: High-throughput phosphoproteome analysis of isolated mitochondria assigning
      DLAT to the mitochondrion. Correct but general compartment.
    action: KEEP_AS_NON_CORE
    reason: Correct mitochondrial localization from a mitochondrial phosphoproteome;
      general compartment, with matrix being the more specific term.
    supported_by:
    - reference_id: PMID:20833797
      supporting_text: functional mitochondria isolated from resting
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15861126
  qualifier: enables
  review:
    summary: IPI capturing the DLAT lipoyl-domain-2/PDK3 interaction (crystal structure
      of PDK3 bound to lipoyl domain 2). Real, structurally defined interaction, but
      uninformative bare term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare "protein binding" is uninformative. The lipoyl-domain-2/PDK3 interaction
      is genuine and structurally characterized, but the term is marked over-annotated
      per policy rather than removed.
    supported_by:
    - reference_id: file:human/DLAT/DLAT-uniprot.txt
      supporting_text: Interacts with PDK2 and PDK3
- term:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase activity
  evidence_type: NAS
  original_reference_id: PMID:3191998
  qualifier: enables
  review:
    summary: NAS from the original human DLAT cDNA sequencing paper, assigning the
      dihydrolipoamide acetyltransferase (E2) identity/activity. Core function, historically
      established.
    action: ACCEPT
    reason: The founding sequence report identifying DLAT as the E2 acetyltransferase
      of the human PDC; consistent with all later experimental evidence.
    supported_by:
    - reference_id: PMID:3191998
      supporting_text: the dihydrolipoamide acetyltransferase
- term:
    id: GO:0045254
    label: pyruvate dehydrogenase complex
  evidence_type: NAS
  original_reference_id: PMID:3191998
  qualifier: part_of
  review:
    summary: NAS from the original DLAT cDNA paper, assigning DLAT as a component of
      the human PDC. Core complex membership, historically established.
    action: ACCEPT
    reason: The founding report describing DLAT as the E2 component of the human PDC;
      consistent with later experimental complex annotations.
    supported_by:
    - reference_id: PMID:3191998
      supporting_text: human pyruvate dehydrogenase complex
core_functions:
- description: Dihydrolipoyllysine-residue acetyltransferase (E2) that transfers the
    acetyl group from the acetyl-dihydrolipoyl-lysine intermediate to coenzyme A,
    forming acetyl-CoA, as the second catalytic step of the pyruvate dehydrogenase
    complex reaction, acting as the structural and catalytic core of the complex in
    the mitochondrial matrix.
  molecular_function:
    id: GO:0004742
    label: dihydrolipoyllysine-residue acetyltransferase 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:20160912
    supporting_text: E2 then transfers the acetyl moiety to CoA forming acetyl-CoA.
  - reference_id: PMID:19240034
    supporting_text: The human PDC is organized around a 60-meric
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: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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15861126
  title: Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain
    2 of human pyruvate dehydrogenase complex.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Structurally characterizes the DLAT lipoyl-domain-2/PDK3 interaction;
      supports the (uninformative) protein-binding IPI but not a core function.
- id: PMID:17683942
  title: Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase
    isoforms by AZD7545, dichloroacetate, and radicicol.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PDK3-inhibitor structural study using DLAT lipoyl domain 2; source
      of a bare protein-binding IPI, peripheral to DLAT's core function.
- id: PMID:18184587
  title: Extended polypeptide linkers establish the spatial architecture of a pyruvate
    dehydrogenase multienzyme complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the E2 central core architecture and the shuttling role
      of E2 lipoyl domains; supports the structural core function.
- id: PMID:18184588
  title: 'Structures of the human pyruvate dehydrogenase complex cores: a highly conserved
    catalytic center with flexible N-terminal domains.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cryo-EM of the human E2 core; identifies E2 as the central component
      forming the PDC catalytic core.
- id: PMID:18206651
  title: Binding of pyruvate dehydrogenase to the core of the human pyruvate dehydrogenase
    complex.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Maps the E1(beta)-E2 subunit-binding interaction; supports E1 assembly
      onto the E2 core.
- 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: Establishes DLAT (E2p) as part of the 60-meric dodecahedral PDC
      core and its stoichiometry.
- id: PMID:20160912
  title: Interaction of E1 and E3 components with the core proteins of the human pyruvate
    dehydrogenase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the UniProt EC 2.3.1.12 catalytic-activity assignment;
      describes E2 transferring the acetyl moiety to CoA to form acetyl-CoA.
- 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: LOW
    correctness: VERIFIED
    review_notes: High-throughput mitochondrial phosphoproteome; supports mitochondrial
      localization only.
- 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 reconstitution of the recombinant human PDC; supports
      DLAT's role in the pyruvate-to-acetyl-CoA reaction and complex membership.
- id: PMID:25525879
  title: Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Identifies DLAT K132/K259 lipoyl sites and the SIRT4 delipoylation
      regulatory mechanism; explicitly states DLAT constitutes the PDH catalytic core.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome (BioPlex); source of a bare protein-binding
      IPI, not informative for core function.
- id: PMID:3191998
  title: Nucleotide sequence of a cDNA for the dihydrolipoamide acetyltransferase
    component of human pyruvate dehydrogenase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding cDNA report identifying DLAT as the E2 (dihydrolipoamide
      acetyltransferase) component of the human PDC.
- 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 3.0); source of bare protein-binding
      IPIs, not informative for core function.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-confidence mitochondrial proteome; supports mitochondrial localization
      only.
- id: PMID:9045657
  title: Assembly and full functionality of recombinantly expressed dihydrolipoyl
    acetyltransferase component of the human pyruvate dehydrogenase complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Recombinant human E2 with high acetyltransferase activity assembling
      into the pentagonal dodecahedron core; supports both catalytic and structural-core
      functions.
- id: PMID:9242632
  title: Dihydrolipoamide dehydrogenase-binding protein of the human pyruvate dehydrogenase
    complex. DNA-derived amino acid sequence, expression, and reconstitution of the
    pyruvate dehydrogenase complex.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Title foregrounds E3BP (protein X), but the full-text reconstitution
      assays the E2 core; the associated IDA/IC annotations to DLAT are curator-derived
      from that work and are accepted.
- 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-9858752
  title: LIPT1 transfers lipoyl group from lipoyl-GCSH to DLAT
  findings: []
- id: Reactome:R-HSA-9861559
  title: PDH complex synthesizes acetyl-CoA from PYR
  findings: []
- id: Reactome:R-HSA-9861616
  title: DLD dimer dehydrogenates dihydrolipoyl
  findings: []
- id: Reactome:R-HSA-9861626
  title: SIRT4 cleaves lipoyl from DLAT
  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: []
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []