id: P36957
gene_symbol: DLST
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DLST is the E2 (dihydrolipoyllysine-residue succinyltransferase, EC 2.3.1.61)
  core component of the mitochondrial 2-oxoglutarate (alpha-ketoglutarate) dehydrogenase
  complex (OGDHC), a megadalton enzyme of the tricarboxylic acid (TCA) cycle assembled
  from the E1 component OGDH, multiple copies of the DLST E2 core, and the shared E3
  component DLD. Within the complex DLST carries a covalently attached lipoyl cofactor
  on an N-terminal lipoyl-binding domain; the lipoyl arm is succinylated by E1 during
  oxidative decarboxylation of 2-oxoglutarate, and DLST then transfers the succinyl
  group to coenzyme A to generate succinyl-CoA. The same DLST E2 core, together with
  the shared DLD E3, also serves the 2-oxoadipate dehydrogenase complex (OADHC) in which
  the DHTKD1 E1 oxidatively decarboxylates 2-oxoadipate; here DLST acts as a
  dihydrolipoyllysine-residue glutaryltransferase forming glutaryl-CoA in the final step
  of L-lysine (and L-tryptophan) catabolism via the saccharopine pathway. DLST is
  predominantly localized to the mitochondrial matrix. A small nuclear fraction of the
  2-oxoglutarate dehydrogenase complex associates with the acetyltransferase KAT2A/GCN5
  on chromatin and provides locally generated succinyl-CoA for histone H3 lysine
  succinylation. Germline loss-of-function variants in DLST cause an autosomal dominant
  pheochromocytoma/paraganglioma predisposition syndrome (PPGL7).
alternative_products:
- name: '1'
  id: P36957-1
- name: '2'
  id: P36957-2
  sequence_note: VSP_056439, VSP_056440
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) assignment of DLST to the mitochondrion. DLST is the E2
      component of the mitochondrial 2-oxoglutarate dehydrogenase complex and is
      predominantly a mitochondrial-matrix protein, consistent with its cleaved
      N-terminal mitochondrial transit peptide (residues 1-67).
    action: ACCEPT
    reason: Correct and well supported by the IBA panel and by direct experimental
      evidence for mitochondrial localization of DLST and the OGDH complex.
    supported_by:
    - reference_id: PMID:30929736
      supporting_text: DLST encodes the E2 subunit of the mitochondrial αKG dehydrogenase
        (OGDH) complex
- term:
    id: GO:0004149
    label: dihydrolipoyllysine-residue succinyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of the core molecular function of DLST, the E2
      succinyltransferase (EC 2.3.1.61) of the 2-oxoglutarate dehydrogenase complex. DLST
      transfers the succinyl group from its dihydrolipoyl arm to coenzyme A to form
      succinyl-CoA. This is the central, defining function of the gene.
    action: ACCEPT
    reason: This is the core catalytic function of DLST, confirmed by the IBA panel, by
      human catalytic-activity/active-site data (His424), and by the well-understood
      OGDHC reaction mechanism.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: E2o transfers the succinyl functional group from its LD domain onto
        CoA-SH generating succinyl-CoA
    - reference_id: PMID:30929736
      supporting_text: The OGDH complex catalyzes the overall conversion of αKG to
        succinyl-CoA and CO
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment of DLST to the TCA cycle. As the E2 of the
      2-oxoglutarate dehydrogenase complex, DLST catalyzes the succinyl-transfer step of
      the cycle; the complex functions directly within the TCA cycle.
    action: ACCEPT
    reason: Core biological process for DLST, strongly supported by the IBA panel and by
      direct experimental evidence.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: OGDHC functions directly within the TCA cycle metabolizing
        2-oxoglutarate to succinyl-CoA, CO2 and NADH + H+ in three consecutive steps
- term:
    id: GO:0004149
    label: dihydrolipoyllysine-residue succinyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (IEA) assignment of the core succinyltransferase molecular function
      via InterPro/RHEA/EC (EC 2.3.1.61, RHEA:15213). Redundant with the experimental IMP,
      IBA, and ISS annotations of the same term.
    action: ACCEPT
    reason: Correct core function; the EC/RHEA mapping matches the experimentally
      established DLST catalytic activity.
    supported_by:
    - reference_id: PMID:30929736
      supporting_text: DLST encodes the E2 subunit of the mitochondrial αKG dehydrogenase
        (OGDH) complex
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated import (IEA) from the UniProt Subcellular Location vocabulary
      (SL-0191, Nucleus). DLST is predominantly a mitochondrial-matrix protein; only a
      small (~1-1.6%) nuclear fraction of the OGDH complex exists, where it supports
      KAT2A-dependent histone succinylation.
    action: KEEP_AS_NON_CORE
    reason: The nuclear pool is real but minor and moonlighting rather than the core
      mitochondrial function; keep as a non-core localization. Verified experimentally
      by KAT2A/histone-succinylation work.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: about 1–1.6% of total OGDH, DLST, and DLD was localized in the
        nucleus
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Automated (IEA) assignment to the mitochondrial matrix, the principal
      compartment where DLST acts as the E2 core of the OGDH complex.
    action: ACCEPT
    reason: Correct and specific core localization; consistent with UniProt subcellular
      location and the soluble matrix-localized nature of the OGDH complex.
    supported_by:
    - reference_id: PMID:30929736
      supporting_text: DLST encodes the E2 subunit of the mitochondrial αKG dehydrogenase
        (OGDH) complex
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Automated (IEA) assignment of DLST to the TCA cycle. Redundant with the
      experimental IMP and phylogenetic IBA annotations of the same term.
    action: ACCEPT
    reason: Core biological process; correct and consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: OGDHC functions directly within the TCA cycle metabolizing
        2-oxoglutarate to succinyl-CoA, CO2 and NADH + H+ in three consecutive steps
- term:
    id: GO:0016746
    label: acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO (IEA) mapping from the 2-oxoacid dehydrogenase acyltransferase
      domain (IPR001078) to the generic parent term acyltransferase activity. The specific
      child term dihydrolipoyllysine-residue succinyltransferase activity (GO:0004149) is
      already annotated with experimental and phylogenetic evidence.
    action: MODIFY
    reason: Not wrong but uninformatively general; the precise molecular function
      (GO:0004149, and GO:0120571 for the OADHC role) is established. Generalize/replace
      with the specific succinyltransferase activity term.
    proposed_replacement_terms:
    - id: GO:0004149
      label: dihydrolipoyllysine-residue succinyltransferase activity
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: E2o transfers the succinyl functional group from its LD domain onto
        CoA-SH generating succinyl-CoA
- term:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Automated (IEA) assignment of DLST as part of the oxoglutarate dehydrogenase
      complex. DLST is the E2 core-forming subunit of this complex.
    action: ACCEPT
    reason: Correct and central; redundant with the experimental IDA and NAS annotations
      of the same term.
    supported_by:
    - reference_id: PMID:30929736
      supporting_text: DLST encodes the E2 subunit of the mitochondrial αKG dehydrogenase
        (OGDH) complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16169070
  qualifier: enables
  review:
    summary: IntAct-derived IPI for a binary interaction (with NAP1L1, P55209) from a
      large-scale automated yeast two-hybrid human interactome screen. The bare term
      protein binding conveys no specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: A single high-throughput Y2H interaction with a nucleosome-assembly protein
      does not define an informative molecular function for DLST; the term protein binding
      is uninformative and this interaction has no established functional role. DLST's
      biologically meaningful partners (OGDH, DLD, KAT2A) are captured by complex and
      process terms.
    supported_by:
    - reference_id: PMID:16169070
      supporting_text: We identified 3186 mostly novel interactions among 1705 proteins,
        resulting in a large, highly connected network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29128334
  qualifier: enables
  review:
    summary: IntAct-derived IPI(s) for interactions detected in an affinity-purification
      mass-spectrometry map of mitochondrial protein interactions (partners include CDK1,
      PSMC4, NAP1L1, YWHAE). The bare term protein binding conveys no specific molecular
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput AP/MS interactions do not establish an informative molecular
      function; protein binding is uninformative per curation guidelines. No specific
      functional consequence for DLST is established for these partners.
    supported_by:
    - reference_id: PMID:29128334
      supporting_text: 'we report a high-confidence MP network including 1,964 interactions
        among 772 proteins (>90% previously unreported)'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: IntAct-derived IPIs for numerous (~70) binary interactions from a
      neurodegenerative-disease yeast two-hybrid interactome map. The bare term protein
      binding conveys no specific molecular function, and the interactors span many
      unrelated proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: A large set of high-throughput Y2H interactions with functionally unrelated
      proteins does not define an informative molecular function; protein binding is
      uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease
        Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
- term:
    id: GO:0120551
    label: 2-oxoglutarate decarboxylation to succinyl-CoA
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-orthology (IEA) assignment to the specific process by which the
      2-oxoglutarate dehydrogenase complex converts 2-oxoglutarate to succinyl-CoA. This
      is precisely the OGDHC reaction in which DLST performs the succinyl-transfer step.
    action: ACCEPT
    reason: Accurate and specific process term for the OGDHC step catalyzed by DLST;
      well supported by the reaction mechanism.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: OGDHC functions directly within the TCA cycle metabolizing
        2-oxoglutarate to succinyl-CoA, CO2 and NADH + H+ in three consecutive steps
- term:
    id: GO:0120571
    label: dihydrolipoyllysine-residue glutaryltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:29191460
  qualifier: enables
  review:
    summary: Experimental (IDA) demonstration that the shared DLST E2 (hE2o), together
      with the shared DLD E3, functions in the 2-oxoadipate dehydrogenase complex assembled
      with the DHTKD1 E1 (hE1a). In this complex DLST acts as a glutaryltransferase,
      transferring the glutaryl group to CoA to form glutaryl-CoA in L-lysine/L-tryptophan
      catabolism.
    action: ACCEPT
    reason: A genuine, distinct molecular function of the same DLST E2 core when serving
      the OADHC; experimentally reconstituted with recombinant human components.
    supported_by:
    - reference_id: PMID:29191460
      supporting_text: The hE1a has recruited the
    - reference_id: PMID:29191460
      supporting_text: specific to the 2-oxoadipate dehydrogenase complex
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: located_in
  review:
    summary: ComplexPortal (NAS) assignment of DLST to the mitochondrion as a subunit of
      the mitochondrial 2-oxoglutarate dehydrogenase complex.
    action: ACCEPT
    reason: Correct; the mitochondrial-matrix term (GO:0005759) is more specific but this
      parent localization is accurate.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: which in eukaryotes are located within mitochondria
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: involved_in
  review:
    summary: ComplexPortal (NAS) assignment of DLST to the TCA cycle as the E2 of the
      2-oxoglutarate dehydrogenase complex. Redundant with the IBA and IMP annotations of
      the same term.
    action: ACCEPT
    reason: Core biological process; correct and well supported.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: OGDHC functions directly within the TCA cycle metabolizing
        2-oxoglutarate to succinyl-CoA, CO2 and NADH + H+ in three consecutive steps
- term:
    id: GO:0006103
    label: 2-oxoglutarate metabolic process
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: involved_in
  review:
    summary: ComplexPortal (NAS) assignment of DLST to 2-oxoglutarate metabolic process.
      The OGDH complex consumes 2-oxoglutarate, converting it to succinyl-CoA; DLST is the
      succinyl-transfer subunit of that reaction.
    action: ACCEPT
    reason: Accurate process term for the OGDHC substrate; consistent with the succinyl-CoA
      generating reaction. Also supported by the ISS annotation of the same term.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: which generates NADH by oxidative decarboxylation
- term:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  evidence_type: NAS
  original_reference_id: PMID:36854377
  qualifier: part_of
  review:
    summary: ComplexPortal (NAS) assignment of DLST as part of the oxoglutarate
      dehydrogenase complex. This paper defines the eukaryotic OGDHC architecture with the
      E2o (DLST) octahedral core. Redundant with the IDA and IEA annotations of the same
      term.
    action: ACCEPT
    reason: Correct and central; DLST forms the core of this complex.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: an octahedral core of 24 E2o subunits
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Human Protein Atlas immunofluorescence (IDA) localization to the nucleoplasm.
      DLST is predominantly mitochondrial; only a small nuclear fraction of the OGDH
      complex exists, where it supports histone succinylation.
    action: KEEP_AS_NON_CORE
    reason: The nuclear/nucleoplasmic pool is genuine but minor and moonlighting, not the
      core function; retain as a non-core localization. Independently supported by focused
      KAT2A/histone-succinylation work.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: about 1–1.6% of total OGDH, DLST, and DLD was localized in the
        nucleus
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput proteomics (HTP) placing DLST in the mitochondrion as part of
      a quantitative high-confidence human mitochondrial proteome.
    action: ACCEPT
    reason: Correct core localization; consistent with the mitochondrial-matrix E2 role of
      DLST.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome
- term:
    id: GO:0160167
    label: oxoadipate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:29191460
  qualifier: part_of
  review:
    summary: Experimental (IDA) demonstration that the shared DLST E2 (hE2o) is part of
      the 2-oxoadipate dehydrogenase complex, assembled with the DHTKD1 E1 (hE1a) and the
      shared DLD E3. This is the second complex served by the same DLST E2 core.
    action: ACCEPT
    reason: A genuine second complex membership for DLST, biochemically reconstituted;
      distinct from the OGDHC and central to L-lysine/L-tryptophan catabolism.
    supported_by:
    - reference_id: PMID:29191460
      supporting_text: The hE1a has recruited the
    - reference_id: PMID:29191460
      supporting_text: specific to the 2-oxoadipate dehydrogenase complex
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858321
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization tied to the 2-oxoadipate
      dehydrogenase (DHTKD1) decarboxylation reaction, where DLST acts as the E2 of the
      OADHC. The matrix is the correct core localization.
    action: ACCEPT
    reason: Correct and specific core localization for the OADHC/OGDHC E2 core.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858590
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization tied to the reaction in which
      DLST transfers the glutaryl group to CoA in the OADHC. The matrix is the correct core
      localization.
    action: ACCEPT
    reason: Correct and specific core localization for the OADHC/OGDHC E2 core.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71401
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization tied to the OGDH-catalyzed
      decarboxylation of 2-oxoglutarate within the OGDH complex. The matrix is the correct
      core localization.
    action: ACCEPT
    reason: Correct and specific core localization for the OGDHC E2 core.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9853499
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization tied to the DLD-catalyzed
      re-oxidation of the dihydrolipoyl arm within the OGDH complex. The matrix is the
      correct core localization.
    action: ACCEPT
    reason: Correct and specific core localization for the OGDHC E2 core.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9853512
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization for the reaction in which
      DLST transfers the succinyl group to CoA within the OGDH complex. The matrix is the
      correct core localization.
    action: ACCEPT
    reason: Correct and specific core localization for the OGDHC E2 core.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858589
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization tied to the DLD-catalyzed
      re-oxidation step in the OADHC. The matrix is the correct core localization.
    action: ACCEPT
    reason: Correct and specific core localization for the OADHC/OGDHC E2 core.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0004149
    label: dihydrolipoyllysine-residue succinyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:30929736
  qualifier: enables
  review:
    summary: Experimental (IMP) support for the core succinyltransferase activity from
      functional evaluation of DLST variants, including the catalytically essential active
      site His424 (H424A abolishes activity) and the disease-associated p.Gly374Glu that
      compromises DLST function and disrupts OGDH complex activity.
    action: ACCEPT
    reason: Directly establishes the core catalytic molecular function of human DLST in
      cells; UniProt cites this paper for EC 2.3.1.61 and active-site His424.
    supported_by:
    - reference_id: PMID:30929736
      supporting_text: Depletion of any of the OGDH complex subunits leads to impaired
        enzymatic activity and αKG accumulation, and it has been demonstrated that DLST is
        a non-redundant member of the OGDH complex.
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: IMP
  original_reference_id: PMID:30929736
  qualifier: involved_in
  review:
    summary: Experimental (IMP) support for DLST involvement in the TCA cycle. DLST-KO
      cells exhibit complete disruption of the oxidative TCA cycle, and DLST variants
      disrupt OGDH complex activity and cause TCA-cycle metabolite (2HG) accumulation.
    action: ACCEPT
    reason: Core biological process, directly demonstrated by loss-of-function studies in
      cells.
    supported_by:
    - reference_id: PMID:30929736
      supporting_text: they exhibit a complete disruption of the oxidative TCA cycle
- term:
    id: GO:0016746
    label: acyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:30929736
  qualifier: enables
  review:
    summary: Experimental (IMP) annotation to the generic parent term acyltransferase
      activity. The specific molecular function, dihydrolipoyllysine-residue
      succinyltransferase activity (GO:0004149), is annotated with the same experimental
      evidence.
    action: MODIFY
    reason: Correct in essence but uninformatively general; the precise succinyltransferase
      activity is the appropriate term. Generalize/replace with GO:0004149.
    proposed_replacement_terms:
    - id: GO:0004149
      label: dihydrolipoyllysine-residue succinyltransferase activity
    supported_by:
    - reference_id: PMID:30929736
      supporting_text: Depletion of any of the OGDH complex subunits leads to impaired
        enzymatic activity and αKG accumulation, and it has been demonstrated that DLST is
        a non-redundant member of the OGDH complex.
- term:
    id: GO:0004149
    label: dihydrolipoyllysine-residue succinyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity (ISS) transfer of the core succinyltransferase activity
      from an ortholog. Redundant with the human IMP, IBA, and IEA annotations of the same
      term.
    action: ACCEPT
    reason: Correct core function, independently confirmed experimentally in human DLST.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: E2o transfers the succinyl functional group from its LD domain onto
        CoA-SH generating succinyl-CoA
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:29211711
  qualifier: located_in
  review:
    summary: Experimental (IDA) nuclear localization of DLST as part of the α-KGDH complex.
      Cell fractionation and immunofluorescence showed ~1-1.6% of DLST (and OGDH, DLD) in
      the nucleus, where the complex couples with KAT2A for histone succinylation; DLST NLS
      residues Arg224/Lys226 mediate nuclear translocation.
    action: KEEP_AS_NON_CORE
    reason: A genuine but minor moonlighting localization; the core function of DLST is
      mitochondrial. Retain as non-core.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: about 1–1.6% of total OGDH, DLST, and DLD was localized in the
        nucleus
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:29211711
  qualifier: located_in
  review:
    summary: Experimental (IDA) mitochondrial localization of DLST. The bulk (~98%) of the
      α-KGDH complex, including DLST, resides in the mitochondrion.
    action: ACCEPT
    reason: Correct core localization; the mitochondrial-matrix term is more specific but
      this is accurate.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: which is a component of the α-KGDH complex that catalyses the
        conversion of α-ketoglutarate (α-KG) to succinyl- CoA
- term:
    id: GO:0006103
    label: 2-oxoglutarate metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity (ISS) transfer of 2-oxoglutarate metabolic process. DLST,
      as the OGDHC E2, consumes 2-oxoglutarate in producing succinyl-CoA. Redundant with
      the NAS annotation of the same term.
    action: ACCEPT
    reason: Accurate process term for the OGDHC substrate; consistent with experimental
      evidence.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: which generates NADH by oxidative decarboxylation
- term:
    id: GO:0006104
    label: succinyl-CoA metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity (ISS) transfer of succinyl-CoA metabolic process. The
      product of the DLST-catalyzed reaction is succinyl-CoA, so DLST directly participates
      in succinyl-CoA metabolism.
    action: ACCEPT
    reason: Accurate process term for the product of the DLST succinyltransferase reaction.
    supported_by:
    - reference_id: PMID:36854377
      supporting_text: E2o transfers the succinyl functional group from its LD domain onto
        CoA-SH generating succinyl-CoA
- term:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  evidence_type: IDA
  original_reference_id: PMID:29211711
  qualifier: part_of
  review:
    summary: Experimental (IDA) demonstration that DLST is part of the α-KGDH (OGDH)
      complex, shown by co-immunoprecipitation of endogenous OGDH, DLST, and DLD. Redundant
      with the NAS and IEA annotations of the same term.
    action: ACCEPT
    reason: Correct and central complex membership, directly demonstrated in human cells.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: which is a component of the α-KGDH complex that catalyses the
        conversion of α-ketoglutarate (α-KG) to succinyl- CoA
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694018
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization tied to a lipoyl/glycine-
      cleavage-system oxidation reaction. The matrix is the correct core localization for
      DLST.
    action: ACCEPT
    reason: Correct and specific core localization.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6792572
  qualifier: located_in
  review:
    summary: Reactome (TAS) mitochondrial-matrix localization tied to LIPT1-mediated lipoyl
      transfer onto DBT/DLST (lipoylation of the E2 lipoyl domain). The matrix is the
      correct core localization for DLST.
    action: ACCEPT
    reason: Correct and specific core localization; consistent with DLST lipoylation in the
      matrix.
    supported_by:
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomics (HDA) placing DLST in a membrane fraction from a
      study defining the NK-cell membrane proteome. DLST is a soluble mitochondrial-matrix
      enzyme with no transmembrane region.
    action: MARK_AS_OVER_ANNOTATED
    reason: DLST has no membrane domain and is a soluble matrix protein; a membrane-fraction
      co-purification does not reflect a genuine membrane localization. This is a
      proteomic-survey artifact and not a core (or accurate) localization.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: Defining the membrane proteome of NK cells.
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: Mitochondrion matrix
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: High-throughput proteomics (HDA) detecting DLST in a human sperm nucleus
      proteome. A genuine nuclear pool of DLST/the OGDH complex exists (per focused KAT2A
      work), but this HDA is a proteomic-survey localization in a specialized cell type.
    action: KEEP_AS_NON_CORE
    reason: The nuclear pool of DLST is real but minor and moonlighting; retain as non-core
      rather than as a defining localization. Independently supported by KAT2A/histone-
      succinylation work.
    supported_by:
    - reference_id: PMID:29211711
      supporting_text: about 1–1.6% of total OGDH, DLST, and DLD was localized in the
        nucleus
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:8009371
  qualifier: involved_in
  review:
    summary: Author-statement (TAS) annotation to the broad process generation of precursor
      metabolites and energy, from the cloning/mapping paper for the human E2k
      (dihydrolipoyl succinyltransferase) of the alpha-ketoglutarate dehydrogenase complex.
      This reflects the TCA-cycle role but at a very general level.
    action: MARK_AS_OVER_ANNOTATED
    reason: Not wrong but uninformatively broad; the specific processes (tricarboxylic acid
      cycle, 2-oxoglutarate metabolic process, 2-oxoglutarate decarboxylation to
      succinyl-CoA) are already annotated with better evidence.
    supported_by:
    - reference_id: PMID:8009371
      supporting_text: alpha-ketoglutarate dehydrogenase complex (KGDHC) from a human fetal
        brain cDNA
- term:
    id: GO:0033512
    label: L-lysine catabolic process to acetyl-CoA via L-saccharopine
  evidence_type: IDA
  original_reference_id: PMID:29191460
  qualifier: involved_in
  review:
    summary: Proposed annotation capturing DLST's role in L-lysine catabolism. As the E2
      of the 2-oxoadipate dehydrogenase complex (with the DHTKD1 E1 and shared DLD E3),
      DLST carries out the final glutaryl-transfer step of the saccharopine pathway of
      L-lysine (and L-tryptophan) degradation, forming glutaryl-CoA. UniProt records this
      pathway (L-lysine degradation via saccharopine; glutaryl-CoA from L-lysine, step
      6/6) and the shared-E2 function was demonstrated experimentally.
    action: NEW
    reason: DLST participates in lysine catabolism via its shared role in the 2-oxoadipate
      dehydrogenase complex; this process is supported by UniProt PATHWAY and by
      experimental reconstitution of the OADHC, and is not otherwise represented in the
      existing annotations.
    supported_by:
    - reference_id: PMID:29191460
      supporting_text: specific to the 2-oxoadipate dehydrogenase complex
    - reference_id: file:human/DLST/DLST-uniprot.txt
      supporting_text: 'Amino-acid degradation; L-lysine degradation via saccharopine'
core_functions:
- description: E2 dihydrolipoyllysine-residue succinyltransferase core of the mitochondrial
    2-oxoglutarate (alpha-ketoglutarate) dehydrogenase complex; transfers the succinyl
    group from its dihydrolipoyl arm to coenzyme A, forming succinyl-CoA in the TCA
    cycle.
  molecular_function:
    id: GO:0004149
    label: dihydrolipoyllysine-residue succinyltransferase activity
  directly_involved_in:
  - id: GO:0006099
    label: tricarboxylic acid cycle
  - id: GO:0006103
    label: 2-oxoglutarate metabolic process
  - id: GO:0006104
    label: succinyl-CoA metabolic process
  in_complex:
    id: GO:0045252
    label: oxoglutarate dehydrogenase complex
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:36854377
    supporting_text: E2o transfers the succinyl functional group from its LD domain onto
      CoA-SH generating succinyl-CoA
  - reference_id: PMID:30929736
    supporting_text: The OGDH complex catalyzes the overall conversion of αKG to
      succinyl-CoA and CO
- description: E2 dihydrolipoyllysine-residue glutaryltransferase core shared with the
    mitochondrial 2-oxoadipate dehydrogenase complex (with the DHTKD1 E1 and shared DLD
    E3); transfers the glutaryl group to coenzyme A forming glutaryl-CoA in the final
    step of L-lysine and L-tryptophan catabolism.
  molecular_function:
    id: GO:0120571
    label: dihydrolipoyllysine-residue glutaryltransferase activity
  directly_involved_in:
  - id: GO:0033512
    label: L-lysine catabolic process to acetyl-CoA via L-saccharopine
  in_complex:
    id: GO:0160167
    label: oxoadipate dehydrogenase complex
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:29191460
    supporting_text: specific to the 2-oxoadipate dehydrogenase complex
  - reference_id: file:human/DLST/DLST-uniprot.txt
    supporting_text: 'Amino-acid degradation; L-lysine degradation via saccharopine'
proposed_new_terms: []
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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16169070
  title: 'A human protein-protein interaction network: a resource for annotating the
    proteome.'
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- 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: []
- id: PMID:29191460
  title: The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes
    share their E2 and E3 components for their function and both generate reactive
    oxygen species.
  findings: []
- id: PMID:29211711
  title: KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.
  findings: []
- id: PMID:30929736
  title: Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas
    and Paragangliomas.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:36854377
  title: MRPS36 provides a structural link in the eukaryotic 2-oxoglutarate dehydrogenase
    complex.
  findings: []
- id: PMID:8009371
  title: Isolation, characterization, and mapping of gene encoding dihydrolipoyl succinyltransferase
    (E2k) of human alpha-ketoglutarate dehydrogenase complex.
  findings: []
- id: Reactome:R-HSA-5694018
  title: DLD dimer:2xFAD oxidises GCSH:DHLL to GCSH:lipoate
  findings: []
- id: Reactome:R-HSA-6792572
  title: LIPT1 transfers lipoyl group from lipoyl-GCSH to DBT/DLST
  findings: []
- id: Reactome:R-HSA-71401
  title: OGDH dimer decarboxylates 2-OG
  findings: []
- id: Reactome:R-HSA-9853499
  title: DLD dimer dehydrogenates dihydrolipoyl
  findings: []
- id: Reactome:R-HSA-9853512
  title: DLST transfers succinyl to CoA
  findings: []
- id: Reactome:R-HSA-9858321
  title: DHTKD1 dimer decarboxylates 2-OA
  findings: []
- id: Reactome:R-HSA-9858589
  title: DLD dimer dehydrogenates dihydrolipoyl
  findings: []
- id: Reactome:R-HSA-9858590
  title: DLST transfers glutaryl to CoA
  findings: []