id: P09110
gene_symbol: ACAA1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ACAA1 (peroxisomal 3-ketoacyl-CoA thiolase; peroxisomal thiolase 1) is a peroxisomal-matrix
  enzyme that catalyzes the final, thiolytic-cleavage step of the peroxisomal fatty-acid
  beta-oxidation spiral. Using coenzyme A, it cleaves a 3-oxoacyl-CoA (3-ketoacyl-CoA) into an
  acyl-CoA shortened by two carbons plus acetyl-CoA (acetyl-CoA C-acyltransferase / 3-ketoacyl-CoA
  thiolase, EC 2.3.1.16). It acts on straight-chain substrates across short, medium, long, and
  very-long chain lengths in the ACOX1/EHHADH-HSD17B4 spiral, whereas the branched-chain and
  bile-acid thiolytic step is carried by the separate SCPx/SCP2 thiolase. Through this activity
  ACAA1 supports degradation of very-long-chain fatty acids and contributes to peroxisomal
  chain-shortening reactions in polyunsaturated fatty acid metabolism, including the retroconversion
  of C24:6n-3 to docosahexaenoic acid (DHA). ACAA1 is synthesized in the cytosol with a cleavable
  N-terminal PTS2 targeting signal that is recognized by the receptor PEX7 (with co-receptor PEX5L)
  and mediates import into the peroxisomal matrix, where the signal is removed and the enzyme
  functions as a homodimer. It is expressed broadly with enrichment in liver and kidney, and its
  deficiency impairs peroxisomal beta-oxidation.
alternative_products:
- name: '1'
  id: P09110-1
- name: '2'
  id: P09110-2
  sequence_note: VSP_046195, VSP_046196
existing_annotations:
- term:
    id: GO:0003988
    label: acetyl-CoA C-acyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the core 3-ketoacyl-CoA thiolase (EC 2.3.1.16) activity.
      This is the defining, evolutionarily conserved molecular function of ACAA1: cleaving a
      3-oxoacyl-CoA with CoA to give an acyl-CoA shortened by two carbons plus acetyl-CoA.
    action: ACCEPT
    reason: >-
      Correct and well-supported across all evidence lines (IBA, ISS from rat P21775, Reactome TAS).
      This is the primary core molecular function of the protein.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) placement of ACAA1 activity in the peroxisome. ACAA1 is a peroxisomal-matrix
      enzyme imported via a PTS2 signal.
    action: ACCEPT
    reason: >-
      Correct core localization, corroborated by multiple experimental IDA studies and UniProt SUBCELL.
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment to fatty acid beta-oxidation, the core biological process ACAA1
      participates in as the thiolase (final) step of the peroxisomal beta-oxidation spiral.
    action: ACCEPT
    reason: >-
      Core process, supported experimentally (IMP) in human thiolase-deficiency studies and by UniProt PATHWAY.
- term:
    id: GO:0010124
    label: phenylacetate catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      IBA propagation of a phenylacetate catabolic process from the thiolase phylogenetic family.
      Phenylacetate degradation via a beta-oxidation-like route is a bacterial/plant pathway; there is
      no evidence that human ACAA1 functions in phenylacetate catabolism.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated from distant family members; not a demonstrated human ACAA1 function. Retained
      (not removed) as it derives from an evolutionary model, but flagged as an over-annotation.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - LINEAGE_OR_TAXON_MISMATCH
      - FUNCTIONAL_DIVERGENCE
- term:
    id: GO:0003985
    label: acetyl-CoA C-acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (RHEA/EC 2.3.1.9) assignment of acetoacetyl-CoA thiolase activity (2 acetyl-CoA =
      acetoacetyl-CoA + CoA). UniProt lists this reaction only by similarity to rat (P21775); it is a
      minor/ancestral short-chain condensation activity, not the principal function of ACAA1.
    action: KEEP_AS_NON_CORE
    reason: >-
      Chemically plausible for a thiolase-family enzyme but non-core; the principal activity is the
      3-ketoacyl-CoA thiolase (GO:0003988) direction of degradative chain shortening.
- term:
    id: GO:0003988
    label: acetyl-CoA C-acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (RHEA/EC 2.3.1.16) assignment of the core 3-ketoacyl-CoA thiolase activity, matching
      the many curated catalytic-activity reactions in UniProt.
    action: ACCEPT
    reason: >-
      Correct core molecular function, redundant with the IBA/ISS/TAS calls to the same term.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniProt SubCell SL-0204 / ARBA) peroxisome localization, consistent with the
      experimentally established localization.
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0016746
    label: acyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IEA) generic acyltransferase activity from the thiolase-like superfamily signature.
      Correct at the family level but far more general than the specific EC 2.3.1.16 thiolase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative parent of the specific acetyl-CoA C-acyltransferase activity (GO:0003988); superseded
      by the specific term.
- term:
    id: GO:0016747
    label: acyltransferase activity, transferring groups other than amino-acyl groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IEA) generic acyltransferase activity from thiolase InterPro signatures. Correct but
      overly broad relative to the specific 3-ketoacyl-CoA thiolase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative parent term superseded by GO:0003988.
- term:
    id: GO:0050633
    label: acetyl-CoA C-myristoyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (RHEA/EC 2.3.1.155) assignment of a specific-chain-length instance of the thiolase
      reaction (tetradecanoyl-CoA + acetyl-CoA = 3-oxohexadecanoyl-CoA + CoA). This is a legitimate
      substrate of ACAA1 but overly specific; it is one instance of the general straight-chain thiolase
      activity captured by GO:0003988.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct chemistry but an unnecessarily narrow, chain-length-specific term; subsumed by the core
      acetyl-CoA C-acyltransferase activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI from a high-throughput binary interactome screen (HuRI, Y2H), reporting
      an interaction with TFCP2 (Q12800). No functional/mechanistic context is provided and the interaction
      has no established relationship to ACAA1's thiolase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare protein-binding call from a systematic screen; not indicative of a specific
      molecular function. Retained per policy (not removed).
- term:
    id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390247
  qualifier: involved_in
  review:
    summary: >-
      Reactome (TAS) assignment to the peroxisomal (acyl-CoA-oxidase-initiated) branch of fatty acid
      beta-oxidation, via the "Beta-oxidation of very long chain fatty acids" pathway. This is the correct
      peroxisomal specialization of the beta-oxidation process, of which ACAA1 catalyzes the thiolase step.
    action: ACCEPT
    reason: >-
      Accurately captures the peroxisomal (H2O2-generating, oxidase-initiated) beta-oxidation pathway that
      ACAA1 completes.
- term:
    id: GO:0036109
    label: alpha-linolenic acid metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2046106
  qualifier: involved_in
  review:
    summary: >-
      Reactome (TAS) assignment to alpha-linolenic acid (ALA, C18:3n-3) metabolism. ACAA1 participates in
      the peroxisomal beta-oxidation chain-shortening of the C24:6n-3 intermediate to DHA within n-3 PUFA
      metabolism derived from ALA.
    action: KEEP_AS_NON_CORE
    reason: >-
      A specific downstream pathway context of the core beta-oxidation function; correct but a specialized
      process rather than the enzyme's primary annotated role.
- term:
    id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway (IEA) mapping to the peroxisomal acyl-CoA-oxidase-initiated beta-oxidation pathway. Same
      correct process as the Reactome TAS call to this term.
    action: ACCEPT
    reason: >-
      Correct peroxisomal beta-oxidation process; redundant with the TAS annotation.
- term:
    id: GO:0003988
    label: acetyl-CoA C-acyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390250
  qualifier: enables
  review:
    summary: >-
      Reactome (TAS) assignment of the 3-ketoacyl-CoA thiolase activity to the specific reaction
      3-ketohexacosanoyl-CoA + CoA => tetracosanoyl-CoA + acetyl-CoA, an instance of the core thiolase step.
    action: ACCEPT
    reason: Core molecular function, redundant with the IBA/ISS/IEA calls to GO:0003988.
- term:
    id: GO:0008775
    label: acetate CoA-transferase activity
  evidence_type: EXP
  original_reference_id: PMID:11734571
  qualifier: enables
  review:
    summary: >-
      "Acetate CoA-transferase activity" (acyl-CoA + acetate = fatty acid + acetyl-CoA) is a CoA-transferase
      reaction, which is NOT the thiolytic reaction ACAA1 catalyzes (acyl-CoA + acetyl-CoA = 3-oxoacyl-CoA +
      CoA). PMID:11734571 identifies 3-ketoacyl-CoA thiolase and SCPx as the thiolases in DHA-forming
      peroxisomal beta-oxidation; it does not establish a CoA-transferase activity for ACAA1. This is a
      mis-typed molecular function (a Reactome-derived EXP call).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Wrong molecular-function class (CoA-transferase rather than thiolase). Per policy, an EXP annotation is
      not removed; flagged as over-annotation. The correct activity is acetyl-CoA C-acyltransferase (GO:0003988).
    supported_by:
    - reference_id: PMID:11734571
      supporting_text: >-
        SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. These findings are of
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA, IDA) peroxisome localization. Consistent with the established
      peroxisomal-matrix localization of ACAA1.
    action: ACCEPT
    reason: Correct core localization supported by direct imaging.
- term:
    id: GO:0003985
    label: acetyl-CoA C-acetyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer (from rat P21775) of acetoacetyl-CoA thiolase activity (EC 2.3.1.9). A minor/ancestral
      short-chain condensation activity of the thiolase family; not the principal ACAA1 function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Non-core; the core degradative activity is captured by GO:0003988.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:22057399
  qualifier: is_active_in
  review:
    summary: >-
      Direct (IDA) peroxisomal localization from a PTS2/PEX7 import study, in which ACAA1 (acyl-CoA thiolase)
      is treated as a mammalian PTS2-carrying peroxisomal matrix protein that exerts the last step of fatty
      acid beta-oxidation.
    action: ACCEPT
    reason: Correct core localization with mechanistic import support.
    supported_by:
    - reference_id: PMID:22057399
      supporting_text: >-
        acyl-CoA thiolase exerting the last step of fatty acid
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:25538232
  qualifier: is_active_in
  review:
    summary: >-
      Direct (IDA) peroxisomal localization from a PTS2-mediated import study (PEX7-PEX5L-cargo trimeric
      complex), using thiolase as the prototypical PTS2 cargo.
    action: ACCEPT
    reason: Correct core localization; redundant with other IDA/IBA peroxisome calls.
- term:
    id: GO:0003988
    label: acetyl-CoA C-acyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer (from rat P21775) of the core 3-ketoacyl-CoA thiolase (EC 2.3.1.16) activity.
    action: ACCEPT
    reason: Core molecular function; redundant with IBA/IEA/TAS calls to GO:0003988.
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer (from rat P21775) of the fatty acid beta-oxidation process. Core biological process for ACAA1.
    action: ACCEPT
    reason: Core process; redundant with IBA/IMP support.
- term:
    id: GO:0008206
    label: bile acid metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      ISS transfer (from rat P21775) of bile acid metabolic process. The peroxisomal thiolytic step of
      bile-acid (di/trihydroxycholestanoyl-CoA) chain shortening is now attributed principally to the
      separate SCPx/SCP2 thiolase; the ACAA1 bile-acid link derives from early human thiolase-deficiency
      patients that predate that assignment.
    action: KEEP_AS_NON_CORE
    reason: >-
      A secondary/peripheral process for ACAA1 relative to straight-chain beta-oxidation; the branched-chain
      bile-acid thiolase role is carried by SCPx. Retained as non-core rather than removed.
- term:
    id: GO:0050633
    label: acetyl-CoA C-myristoyltransferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS transfer (from rat P21775) of a chain-length-specific instance (EC 2.3.1.155) of the thiolase
      reaction. Overly specific; subsumed by the core acetyl-CoA C-acyltransferase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct chemistry but unnecessarily narrow; non-core relative to GO:0003988.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:19479899
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) peroxisome localization from a peroxisomal-biogenesis study in human fibroblasts.
      Consistent with the established peroxisomal-matrix localization.
    action: ACCEPT
    reason: Correct core localization; one of several redundant IDA peroxisome calls.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033232
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) cytosol localization corresponding to the pre-import state, when PEX7 binds the
      PTS2-containing cytosolic cargo (thiolase) prior to translocation into peroxisomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Reflects a transient trafficking intermediate rather than the compartment where ACAA1 functions; the
      mature, active enzyme is in the peroxisomal matrix.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) cytosol localization for the cytosolic cargo state prior to PEX5L:PEX7-mediated
      translocation into the peroxisomal matrix.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Transient pre-import localization, not the functional compartment; superseded by the peroxisomal-matrix
      annotation.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033514
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) peroxisomal-matrix localization, the compartment where the mature ACAA1 enzyme resides
      and functions after PTS2 cleavage.
    action: ACCEPT
    reason: Correct, most-specific core localization.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798749
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) extracellular-region localization from the neutrophil-degranulation pathway
      ("Exocytosis of specific granule lumen proteins"). ACAA1 has been detected in neutrophil granule
      proteomes, but as a peroxisomal-matrix beta-oxidation enzyme an extracellular localization is not a
      biologically meaningful site of action.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bystander/secretome-proteomics-derived localization; not where ACAA1 performs its molecular function.
- term:
    id: GO:0035580
    label: specific granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798749
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) specific-granule-lumen localization from the neutrophil-degranulation pathway. Based on
      detection of ACAA1 in neutrophil granule proteomes rather than a functional role there.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Proteomics co-detection in neutrophil granules; not the functional peroxisomal compartment.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HDA) membrane-proteome detection (NK-cell membrane proteome). ACAA1 is a soluble
      peroxisomal-matrix enzyme; a "membrane" assignment most likely reflects co-fractionation/contamination
      in a large-scale proteomic dataset.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Spurious/high-throughput localization inconsistent with the soluble matrix biology of ACAA1.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2066788
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) peroxisomal-matrix localization from the "Formation of DHA-CoA catalysed by
      3-ketoacyl-CoA thiolase" reaction, i.e. the matrix compartment where ACAA1 acts.
    action: ACCEPT
    reason: Correct, most-specific core localization.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390250
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) peroxisomal-matrix localization associated with a specific VLCFA thiolase reaction.
    action: ACCEPT
    reason: Correct core localization; redundant with other matrix calls.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9053548
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) peroxisome localization by immunocytochemistry in human liver and kidney.
    action: ACCEPT
    reason: Correct core localization; one of several redundant experimental peroxisome calls.
- term:
    id: GO:0000038
    label: very long-chain fatty acid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:2318981
  qualifier: involved_in
  review:
    summary: >-
      IMP from a patient lacking immunoreactive peroxisomal thiolase, in whom accumulation of C27
      bile-acid intermediates and impaired peroxisomal chain shortening implicate ACAA1 in the metabolism of
      very-long-chain (and cholestanoic) acyl chains. Consistent with the thiolase completing VLCFA
      beta-oxidation.
    action: ACCEPT
    reason: >-
      Correct, experimentally supported process directly downstream of the core thiolase activity.
    supported_by:
    - reference_id: PMID:2318981
      supporting_text: >-
        liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase
- term:
    id: GO:0008206
    label: bile acid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:2318981
  qualifier: involved_in
  review:
    summary: >-
      IMP from bile-acid profiling of a thiolase-deficient patient showing accumulation of C27 bile-acid
      intermediates (varanic acid, THCA). The peroxisomal bile-acid (branched-chain cholestanoyl-CoA)
      thiolytic step is now attributed principally to SCPx/SCP2; this early single-patient link predates that
      assignment.
    action: KEEP_AS_NON_CORE
    reason: >-
      Secondary process relative to straight-chain beta-oxidation; the branched-chain/bile-acid thiolase role
      is carried by SCPx. Retained (experimental) as non-core.
    supported_by:
    - reference_id: PMID:2318981
      supporting_text: >-
        liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IMP
  original_reference_id: PMID:2365812
  qualifier: involved_in
  review:
    summary: >-
      IMP from RCDP fibroblasts with impaired maturation of peroxisomal 3-oxoacyl-CoA thiolase: reduced
      thiolase activity decreases the rate of peroxisomal beta-oxidation of palmitoyl-CoA, directly
      implicating ACAA1 in peroxisomal fatty acid beta-oxidation.
    action: ACCEPT
    reason: >-
      Correct, experimentally supported core process.
    supported_by:
    - reference_id: PMID:2365812
      supporting_text: >-
        results in a decrease in the rate of peroxisomal
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:1347505
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) peroxisome localization from a subcellular-fractionation study in fibroblasts.
    action: ACCEPT
    reason: Correct core localization; redundant with other IDA peroxisome calls.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:2365812
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) peroxisome localization: thiolase activity/protein detected in catalase-containing
      (peroxisomal) fractions in the RCDP-thiolase study.
    action: ACCEPT
    reason: Correct core localization with fractionation support.
    supported_by:
    - reference_id: PMID:2365812
      supporting_text: >-
        results in a decrease in the rate of peroxisomal
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:2895531
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) peroxisome localization by immunocytochemistry of peroxisomal enzymes in human kidney biopsies.
    action: ACCEPT
    reason: Correct core localization; redundant with other IDA peroxisome calls.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:17881773
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) peroxisome localization from a study of peroxisomal-protein expression in human and mouse testis.
    action: ACCEPT
    reason: Correct core localization; redundant with other IDA peroxisome calls.
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IMP
  original_reference_id: PMID:2882519
  qualifier: involved_in
  review:
    summary: >-
      IMP from the first human peroxisomal 3-oxoacyl-CoA thiolase deficiency: peroxisomal beta-oxidation of
      [14C]palmitoyl-CoA was <10% of control and was restored by adding purified rat-liver peroxisomal
      thiolase, directly demonstrating ACAA1's role in peroxisomal fatty acid beta-oxidation.
    action: ACCEPT
    reason: >-
      Definitive experimental support for the core beta-oxidation process.
    supported_by:
    - reference_id: PMID:2882519
      supporting_text: >-
        the deficiency of peroxisomal 3-oxoacyl-CoA thiolase is responsible for the very low peroxisomal beta-oxidation activity
- term:
    id: GO:0120524
    label: long-chain fatty acyl-CoA oxidase activity
  evidence_type: IMP
  original_reference_id: PMID:2882519
  qualifier: enables
  review:
    summary: >-
      "Long-chain fatty acyl-CoA oxidase activity" (acyl-CoA + O2 = enoyl-CoA + H2O2) is the acyl-CoA oxidase
      (ACOX1) step, not the thiolytic step ACAA1 catalyzes. PMID:2882519 measured a thiolase DEFICIENCY (and
      the resulting drop in overall beta-oxidation), not an oxidase activity of ACAA1. This is a mis-typed
      molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Wrong molecular-function class (oxidase rather than thiolase). Per policy, an IMP annotation is not
      removed; flagged as over-annotation. The correct activity is acetyl-CoA C-acyltransferase (GO:0003988).
    supported_by:
    - reference_id: PMID:2882519
      supporting_text: >-
        peroxisomal 3-oxoacyl-CoA thiolase (acyl-CoA:acetyl-CoA C-acyltransferase, EC 2.3.1.16) was
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18281296
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" IPI (with LONP2/pLon, Q86WA8). The cited study actually reports that pLon does
      NOT process the PTS2-containing 3-ketoacyl-CoA thiolase, i.e. it is largely a negative result for a
      functional pLon-thiolase interaction. No informative molecular function is conveyed.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative bare protein-binding call with weak/negative supporting evidence; retained per policy
      (not removed) but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:18281296
      supporting_text: >-
        does not process PTS2-containing
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      InterPro2GO pipeline; yields correct-but-generic acyltransferase terms superseded by the specific
      thiolase activity.
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      ISS transfer from rat peroxisomal thiolase (UniProtKB:P21775); recovers the core thiolase activity,
      beta-oxidation process, and peroxisome localization, plus non-core acetoacetyl-CoA/myristoyltransferase
      and bile-acid annotations.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PAN-GO/IBA pipeline; correctly recovers core thiolase activity, peroxisome, and fatty acid
      beta-oxidation, but also over-propagates phenylacetate catabolic process.
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: UniPathway mapping to peroxisomal beta-oxidation; correct process.
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: HPA immunofluorescence; correct peroxisome localization.
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      RHEA/EC-based electronic annotation; recovers the core thiolase activity and peroxisome localization
      plus non-core acetoacetyl-CoA/myristoyltransferase activities.
- id: PMID:11734571
  title: Identification of the peroxisomal beta-oxidation enzymes involved in the
    biosynthesis of docosahexaenoic acid.
  findings:
  - statement: >-
      The peroxisomal beta-oxidation of C24:6n-3 to C22:6n-3 (DHA) is catalyzed by SCOX (acyl-CoA oxidase),
      DBP (D-bifunctional protein), and both 3-ketoacyl-CoA thiolase (ACAA1) and SCPx, implicating ACAA1 in
      peroxisomal PUFA chain shortening.
    supporting_text: >-
      SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. These findings are of
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache; establishes ACAA1's role (alongside SCPx) in DHA-forming peroxisomal
      beta-oxidation. Note the Reactome-derived EXP "acetate CoA-transferase" annotation to this PMID is a
      mis-typed MF (the paper describes thiolase, not CoA-transferase, activity).
- id: PMID:1347505
  title: Subcellular localisation and processing of non-specific lipid transfer protein
    are not aberrant in Rhizomelic Chondrodysplasia Punctata fibroblasts.
  findings:
  - statement: Peroxisomal thiolase is localized to peroxisomes in human fibroblasts by subcellular fractionation.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only in cache; supports peroxisome localization (IDA).
- id: PMID:17881773
  title: 'Peroxisomes in human and mouse testis: differential expression of peroxisomal
    proteins in germ cells and distinct somatic cell types of the testis.'
  findings:
  - statement: ACAA1/peroxisomal thiolase is expressed in peroxisomes of testicular cells.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only in cache; supports peroxisome localization (IDA).
- id: PMID:18281296
  title: Contribution of peroxisome-specific isoform of Lon protease in sorting PTS1
    proteins to peroxisomes.
  findings:
  - statement: >-
      pLon (peroxisomal Lon/LONP2) does NOT process the PTS2-containing 3-ketoacyl-CoA thiolase, indicating
      no functional pLon-mediated processing of ACAA1.
    supporting_text: >-
      does not process PTS2-containing
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Abstract-only in cache. Cited by GOA as a "protein binding" IPI for ACAA1, but the paper's finding is
      essentially negative (pLon does not process thiolase); the bare protein-binding annotation is
      uninformative/over-annotated.
- id: PMID:19479899
  title: Pex3p-dependent peroxisomal biogenesis initiates in the endoplasmic reticulum
    of human fibroblasts.
  findings:
  - statement: ACAA1/peroxisomal thiolase localizes to peroxisomes in human fibroblasts.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only in cache; supports peroxisome localization (IDA).
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings:
  - statement: >-
      ACAA1 was detected in a high-throughput NK-cell membrane proteome, yielding a generic "membrane"
      localization that is inconsistent with its soluble peroxisomal-matrix biology.
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Abstract-only in cache; high-throughput membrane-proteomics co-detection producing a spurious membrane
      localization for a soluble matrix enzyme.
- id: PMID:22057399
  title: Structural requirements for interaction of peroxisomal targeting signal 2
    and its receptor PEX7.
  findings:
  - statement: >-
      ACAA1 (acyl-CoA thiolase) is a mammalian PTS2-carrying peroxisomal matrix protein that exerts the last
      step of fatty acid beta-oxidation and is imported via interaction of its N-terminal PTS2 with PEX7.
    supporting_text: >-
      acyl-CoA thiolase exerting the last step of fatty acid
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; supports peroxisome localization (IDA) and the PTS2/PEX7 import mechanism, and
      frames ACAA1 as the terminal (thiolase) enzyme of beta-oxidation.
- id: PMID:2318981
  title: Bile acid profiles in peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency.
  findings:
  - statement: >-
      A patient whose liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase accumulated C27
      bile-acid intermediates (varanic acid, THCA), implicating ACAA1 in VLCFA/cholestanoic acid metabolism.
    supporting_text: >-
      liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache; supports very-long-chain fatty acid metabolic process (IMP) and (non-core)
      bile acid metabolic process, though the bile-acid thiolase role is now attributed to SCPx.
- id: PMID:2365812
  title: Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzyme A
    thiolase in peroxisomes and impaired processing of the enzyme.
  findings:
  - statement: >-
      Reduced peroxisomal 3-oxoacyl-CoA thiolase activity decreases the rate of peroxisomal beta-oxidation of
      palmitoyl-CoA, and thiolase is detected in catalase-containing (peroxisomal) fractions.
    supporting_text: >-
      results in a decrease in the rate of peroxisomal
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache; supports fatty acid beta-oxidation (IMP) and peroxisome localization (IDA).
- id: PMID:25538232
  title: 'Mechanistic insights into PTS2-mediated peroxisomal protein import: the
    co-receptor PEX5L drastically increases the interaction strength between the cargo
    protein and the receptor PEX7.'
  findings:
  - statement: >-
      Thiolase is used as the prototypical PTS2 cargo whose import into the peroxisomal matrix requires a
      trimeric PEX7-PEX5L-cargo complex.
    supporting_text: >-
      PTS2-carrying proteins interact with their cognate receptor protein PEX7
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text available; supports peroxisome localization (IDA) via the PTS2/PEX7-PEX5L import mechanism.
- id: PMID:2882519
  title: Human peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency.
  findings:
  - statement: >-
      Deficiency of human peroxisomal 3-oxoacyl-CoA thiolase (acyl-CoA:acetyl-CoA C-acyltransferase, EC
      2.3.1.16) causes very low peroxisomal beta-oxidation activity and accumulation of very-long-chain fatty
      acids and bile-acid intermediates; adding purified thiolase restored beta-oxidation.
    supporting_text: >-
      the deficiency of peroxisomal 3-oxoacyl-CoA thiolase is responsible for the very low peroxisomal beta-oxidation activity
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract/full-abstract in cache; the foundational human genetic evidence for ACAA1's role in
      peroxisomal fatty acid beta-oxidation and EC 2.3.1.16 identity. The GO:0120524 (oxidase) IMP call to
      this PMID is a mis-typed MF (over-annotation).
- id: PMID:2895531
  title: Immunocytochemical demonstration of peroxisomal enzymes in human kidney biopsies.
  findings:
  - statement: Peroxisomal thiolase is demonstrated in peroxisomes of human kidney by immunocytochemistry.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only in cache; supports peroxisome localization (IDA).
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      High-throughput binary (Y2H) interactome mapping reported ACAA1 interactions (with TFCP2 and FEM1A),
      the source of two IntAct bare "protein binding" annotations.
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Full text available; systematic Y2H screen with no functional context for the ACAA1 interactions, so
      the derived bare protein-binding annotations are uninformative/over-annotated.
- id: PMID:9053548
  title: Immunocytochemical localization of peroxisomal proteins in human liver and
    kidney.
  findings:
  - statement: Peroxisomal thiolase localizes to peroxisomes in human liver and kidney by immunocytochemistry.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only in cache; supports peroxisome localization (IDA).
- id: Reactome:R-HSA-2046106
  title: alpha-linolenic acid (ALA) metabolism
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Reactome pathway; ACAA1 participates in peroxisomal chain-shortening within n-3 PUFA metabolism.
- id: Reactome:R-HSA-2066788
  title: Formation of DHA-CoA catalysed by 3-ketoacyl-CoA thiolase
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction directly attributing DHA-CoA formation to the ACAA1 thiolase step in the peroxisomal matrix.
- id: Reactome:R-HSA-390247
  title: Beta-oxidation of very long chain fatty acids
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome pathway for peroxisomal VLCFA beta-oxidation, the core process ACAA1 completes.
- id: Reactome:R-HSA-390250
  title: 3-ketohexacosanoyl-CoA + CoASH => tetracosanoyl-CoA + acetyl-CoA
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction encoding the ACAA1 thiolase step on a specific VLCFA substrate.
- id: Reactome:R-HSA-6798749
  title: Exocytosis of specific granule lumen proteins
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Reactome neutrophil-degranulation pathway; source of extracellular-region and specific-granule-lumen
      localizations that are bystander/proteomics-based, not functional sites for ACAA1.
- id: Reactome:R-HSA-9033232
  title: PEX7 binds cargo proteins containing PTS2
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction for the cytosolic PTS2-cargo recognition step; source of a transient cytosol
      localization, not the functional compartment.
- id: Reactome:R-HSA-9033514
  title: Cargo of PEX5L:PEX7 translocates from the cytosol to the peroxisomal matrix
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome translocation reaction; source of both a transient cytosol localization and the correct
      peroxisomal-matrix localization.
core_functions:
- description: >-
    Peroxisomal 3-ketoacyl-CoA thiolase activity: using coenzyme A, ACAA1 cleaves a straight-chain
    3-oxoacyl-CoA (3-ketoacyl-CoA) into an acyl-CoA shortened by two carbons plus acetyl-CoA (EC
    2.3.1.16), the final step of each round of the peroxisomal fatty-acid beta-oxidation spiral. It
    acts on short-, medium-, long-, and very-long-chain straight substrates and functions as a
    homodimer in the peroxisomal matrix.
  molecular_function:
    id: GO:0003988
    label: acetyl-CoA C-acyltransferase activity
  directly_involved_in:
  - id: GO:0006635
    label: fatty acid beta-oxidation
  - id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  locations:
  - id: GO:0005782
    label: peroxisomal matrix
  supported_by:
  - reference_id: file:human/ACAA1/ACAA1-uniprot.txt
    supporting_text: >-
      Responsible for the thiolytic cleavage of straight chain 3-
  - reference_id: file:human/ACAA1/ACAA1-uniprot.txt
    supporting_text: >-
      Reaction=an acyl-CoA + acetyl-CoA = a 3-oxoacyl-CoA + CoA
  - reference_id: PMID:2882519
    supporting_text: >-
      the deficiency of peroxisomal 3-oxoacyl-CoA thiolase is responsible for the very low peroxisomal beta-oxidation activity
  - reference_id: PMID:2365812
    supporting_text: >-
      results in a decrease in the rate of peroxisomal