id: Q15067
gene_symbol: ACOX1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ACOX1 is the human peroxisomal straight-chain acyl-CoA oxidase 1 (palmitoyl-CoA
  oxidase / SCOX / AOX), an FAD-dependent flavoenzyme that catalyzes the first and
  rate-limiting step of peroxisomal fatty-acid beta-oxidation. It dehydrogenates
  straight-chain (including very-long-chain) 2,3-saturated fatty acyl-CoAs to the
  corresponding (2E)-2-trans-enoyl-CoAs and, unlike the mitochondrial acyl-CoA
  dehydrogenases, transfers the abstracted electrons directly to molecular oxygen,
  producing hydrogen peroxide. Through this activity it initiates the degradation of
  very-long-chain fatty acids and also oxidizes eicosanoid (e.g. prostaglandin) CoA
  esters and long-chain dicarboxylyl-CoAs, and contributes to peroxisomal steps of
  polyunsaturated fatty acid (e.g. DHA) biosynthesis. The enzyme is a homodimer that
  binds FAD as cofactor, is imported into the peroxisomal matrix via its C-terminal
  PTS1 (SKL) signal, and is proteolytically processed into A/B/C chains. Alternative
  splicing yields isoforms with different chain-length preferences (isoform 1 favours
  medium-chain, isoform 2 acts broadly on long- and very-long-chain substrates). Loss
  of ACOX1 activity causes peroxisomal acyl-CoA oxidase deficiency (pseudo-neonatal
  adrenoleukodystrophy) with very-long-chain fatty acid accumulation, whereas a
  recurrent de novo gain-of-function variant (p.N237S) produces a distinct toxic,
  hyperstable homodimer causing the axonal neuropathy Mitchell syndrome.
alternative_products:
- name: 1 (ACOX1a, SCOX-exon 3I)
  id: Q15067-1
- name: 2 (ACOX1b, SCOX-exon 3II)
  id: Q15067-2
  sequence_note: VSP_000146
- name: '3'
  id: Q15067-3
  sequence_note: VSP_046129, VSP_000146
existing_annotations:
- term:
    id: GO:0005504
    label: fatty acid binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically-propagated fatty acid binding. ACOX1 acts on fatty acyl-CoA
      thioesters, not free fatty acids, and there is no evidence it functions as a
      fatty-acid-binding transport/carrier protein. This is an over-annotation of an
      enzyme that binds its acyl-CoA substrate.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Substrate is fatty acyl-CoA, not free fatty acid; 'fatty acid binding' is not an
      informative molecular function for this oxidase and its catalytic activity is
      captured by acyl-CoA oxidase activity.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      source_entities:
      - source_id: PANTHER:PTN000097533
        comment: >-
          Acyl-CoA oxidase family node; members bind fatty acyl-CoA substrates, not free
          fatty acids, so 'fatty acid binding' mis-scopes an enzymatic substrate
          interaction as a standalone binding function.
- term:
    id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Correct core process. ACOX1 is the acyl-CoA oxidase that initiates the peroxisomal
      beta-oxidation spiral, exactly the process described by this term.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: >-
        Involved in the initial and rate-limiting step of peroxisomal
- term:
    id: GO:0120524
    label: long-chain fatty acyl-CoA oxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Chain-length-resolved refinement of acyl-CoA oxidase activity. Consistent with
      isoform 2 acting on long-chain acyl-CoAs and with the documented long-chain
      substrate reactions.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: >-
        shows activity towards long-chain and very-long-chain
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Correct core location. ACOX1 is a peroxisomal matrix flavoenzyme imported via its
      C-terminal PTS1 (SKL) signal.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Correct core cofactor binding. ACOX1 is an FAD-dependent flavoprotein; FAD is
      required for the acyl-CoA oxidase reaction.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Name=FAD; Xref=ChEBI:CHEBI:57692;
- term:
    id: GO:0000038
    label: very long-chain fatty acid metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Correct. ACOX1 initiates degradation of very-long-chain fatty acids; loss of
      activity causes VLCFA accumulation.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: >-
        beta-oxidation of straight-chain saturated and unsaturated very-long-
- term:
    id: GO:0003997
    label: acyl-CoA oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Core molecular function, also supported by multiple experimental annotations.
      This is the defining enzymatic activity of ACOX1.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: >-
        donates electrons directly to molecular oxygen
- term:
    id: GO:0005504
    label: fatty acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based fatty acid binding. Same over-annotation as the IBA fatty acid
      binding annotation: the enzyme binds acyl-CoA substrates, not free fatty acids.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Redundant, uninformative binding term; the substrate is fatty acyl-CoA and the
      relevant activity is acyl-CoA oxidase activity.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Correct core location, redundant with experimental peroxisome annotations.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      Correct and more precise than the parent 'peroxisome' term. ACOX1 is a soluble
      matrix enzyme imported via PTS1.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0006631
    label: fatty acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Correct but very general. The specific role is fatty acid beta-oxidation, which is
      captured by more informative child terms in this annotation set.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-level ancestor of the specific beta-oxidation processes already annotated;
      uninformative on its own.
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Correct core process. ACOX1 catalyzes the first (oxidase) step of the
      beta-oxidation spiral.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: >-
        Involved in the initial and rate-limiting step of peroxisomal
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      Correct but uninformative root-level oxidoreductase term; a distant ancestor of
      the specific acyl-CoA oxidase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Redundant high-level parent of acyl-CoA oxidase activity.
- term:
    id: GO:0016627
    label: oxidoreductase activity, acting on the CH-CH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Correct but uninformative ancestor. Acyl-CoA oxidase acts on the C2-C3 (CH-CH)
      bond, but the specific term acyl-CoA oxidase activity is preferred.
    action: MARK_AS_OVER_ANNOTATED
    reason: Ancestor of the specific acyl-CoA oxidase activity term.
- term:
    id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Correct core process, redundant with the experimental and IBA annotations to this term.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: 'Lipid metabolism; peroxisomal fatty acid beta-oxidation.'
- term:
    id: GO:0044535
    label: very-long-chain fatty acyl-CoA oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Chain-length-resolved refinement of acyl-CoA oxidase activity, based on Rhea
      reactions (e.g. hexacosanoyl-CoA, tetracosanoyl-CoA). Consistent with ACOX1
      initiating VLCFA beta-oxidation.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: >-
        shows activity towards long-chain and very-long-chain
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Correct core cofactor binding, redundant with the IBA FAD-binding annotation.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Name=FAD; Xref=ChEBI:CHEBI:57692;
- term:
    id: GO:0071949
    label: FAD binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Correct core cofactor binding (equivalent to flavin adenine dinucleotide binding).
      ACOX1 is an FAD flavoprotein.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Name=FAD; Xref=ChEBI:CHEBI:57692;
- term:
    id: GO:0120523
    label: medium-chain fatty acyl-CoA oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Chain-length-resolved refinement of acyl-CoA oxidase activity. Isoform 1 shows
      highest activity against medium-chain acyl-CoAs (optimum decanoyl-CoA), supporting
      this Rhea-based annotation.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Shows highest activity against medium-chain
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Correct. The physiological quaternary structure of ACOX1 is a homodimer, confirmed
      by crystal structure and co-immunoprecipitation.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Homodimer (PubMed:32169171).
- term:
    id: GO:0120524
    label: long-chain fatty acyl-CoA oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Chain-length-resolved refinement of acyl-CoA oxidase activity (Rhea-based),
      redundant with the IBA long-chain annotation.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: >-
        shows activity towards long-chain and very-long-chain
- term:
    id: GO:0140493
    label: very long-chain fatty acid beta-oxidation
  evidence_type: IMP
  original_reference_id: PMID:32169171
  qualifier: involved_in
  review:
    summary: >-
      Correct core process, experimentally supported. ACOX1 is the first and
      rate-limiting enzyme of VLCFA beta-oxidation; loss- and gain-of-function variants
      perturb this pathway.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:32169171
      supporting_text: >-
        ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:32169171
  qualifier: is_active_in
  review:
    summary: >-
      Correct core location, directly demonstrated. Wild-type and mutant hACOX1 localize
      to peroxisomes when expressed with a peroxisomal (PTS1) marker.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:32169171
      supporting_text: both hACOX1WT and hACOX1N237S are localized to peroxisomes
- term:
    id: GO:0009062
    label: fatty acid catabolic process
  evidence_type: IMP
  original_reference_id: PMID:32169171
  qualifier: involved_in
  review:
    summary: >-
      Correct. ACOX1 initiates the catabolic (degradative) beta-oxidation of fatty acids;
      the more specific VLCFA beta-oxidation term is also annotated.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:32169171
      supporting_text: >-
        ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:32169171
  qualifier: enables
  review:
    summary: >-
      Correct, experimentally supported. The crystal structure and co-IP data establish
      ACOX1 as a homodimer.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:32169171
      supporting_text: >-
        The crystal structure of ACOX1 revealed that this enzyme acts as a homodimer
        bound to Flavin adenine dinucleotide (FAD)
- term:
    id: GO:0003997
    label: acyl-CoA oxidase activity
  evidence_type: IMP
  original_reference_id: PMID:32169171
  qualifier: enables
  review:
    summary: >-
      Core molecular function, experimentally supported. Enzymatic activity assays
      compared wild-type and mutant ACOX1 and confirm this activity.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:32169171
      supporting_text: >-
        ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the
- term:
    id: GO:0050665
    label: hydrogen peroxide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:32169171
  qualifier: involved_in
  review:
    summary: >-
      Correct and mechanistically central. ACOX1 donates electrons directly to O2,
      producing H2O2; the toxic gain-of-function phenotype is driven by excess
      peroxisomal H2O2 and rescued by catalase.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:32169171
      supporting_text: >-
        H2O2 is reduced by peroxisomal catalase, an abundant peroxisomal enzyme
        responsible for the conversion of H2O2 into O2
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  qualifier: located_in
  review:
    summary: >-
      Reflects the transient pre-import state of newly synthesized ACOX1 during
      PTS1/PEX5-dependent translocation into the peroxisomal matrix, not the site where
      the enzyme acts. Keep as a non-core, transient localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cytosolic localization is the pre-import stage of peroxisomal protein import; the
      functional/catalytic compartment is the peroxisomal matrix.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033236
  qualifier: located_in
  review:
    summary: >-
      Same as the other Reactome cytosol annotation: captures the docking/translocation
      step of peroxisomal import, not the catalytic compartment.
    action: KEEP_AS_NON_CORE
    reason: >-
      Pre-import (docking module) localization; the core functional location is the
      peroxisomal matrix.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9033235
  qualifier: located_in
  review:
    summary: Correct core location; ACOX1 is imported into and acts in the peroxisomal matrix.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      Non-specific high-throughput hit from an NK-cell membrane-proteome study. ACOX1 is
      a soluble peroxisomal matrix enzyme; the membrane preparation retained many
      transiently membrane-associated soluble proteins. Not a meaningful localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic membrane annotation from a proteomics dataset that itself notes many hits
      are soluble proteins transiently associated with membranes; contradicts the
      soluble-matrix localization of ACOX1.
- term:
    id: GO:0030165
    label: PDZ domain binding
  evidence_type: IDA
  original_reference_id: PMID:23209302
  qualifier: enables
  review:
    summary: >-
      The cited paper characterizes the Radil PDZ domain and its interaction with KIF14
      in breast-cancer signaling; the available text does not establish an ACOX1 PDZ
      interaction. ACOX1 does end in the SKL tripeptide, which happens to match the
      atypical Radil PDZ ligand consensus, so ACOX1 may have appeared in a
      motif/BLAST-derived candidate list, but a functional PDZ-binding role is not
      demonstrable from the text available. Cannot verify; leave undecided rather than
      accept or remove an experimental annotation.
    action: UNDECIDED
    reason: >-
      Supporting publication is about Radil/KIF14; ACOX1-specific PDZ-binding evidence is
      not verifiable from the cached full text.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1989749
  qualifier: located_in
  review:
    summary: Correct core location (Reactome 'Expression of ACOX1' pathway context).
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2066787
  qualifier: located_in
  review:
    summary: >-
      Correct core location; annotation derives from a Reactome reaction (oxidation of
      tetracosapentaenoyl-CoA) that ACOX1 catalyzes in the peroxisomal matrix.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390256
  qualifier: located_in
  review:
    summary: >-
      Correct core location; annotation derives from the Reactome reaction 'ACOX1
      oxidizes C26:0 CoA' in the peroxisomal matrix.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:8943006
  qualifier: located_in
  review:
    summary: >-
      Correct core location. This paper primarily characterizes the human branched-chain
      acyl-CoA oxidase (ACOX2) but establishes the two-oxidase division in human liver
      peroxisomes; peroxisomal localization of the straight-chain oxidase (ACOX1) is
      correct.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8943006
      supporting_text: palmitoyl-CoA oxidase, oxidizing very long
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:17881773
  qualifier: located_in
  review:
    summary: >-
      Correct core location; a testis peroxisome study using peroxisomal marker proteins.
      Peroxisomal localization of ACOX1 is well established.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0000038
    label: very long-chain fatty acid metabolic process
  evidence_type: IMP
  original_reference_id: PMID:18536048
  qualifier: involved_in
  review:
    summary: >-
      Correct, experimentally supported by patients with ACOX1 deficiency showing abnormal
      plasma VLCFAs due to loss of straight-chain acyl-CoA oxidase activity.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:18536048
      supporting_text: Plasma very-long-chain fatty acids were abnormal in both
- term:
    id: GO:0003997
    label: acyl-CoA oxidase activity
  evidence_type: IMP
  original_reference_id: PMID:18536048
  qualifier: enables
  review:
    summary: >-
      Core molecular function, supported by patient fibroblasts showing deficiency of the
      straight-chain acyl-CoA oxidase (ACOX1).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:18536048
      supporting_text: >-
        one of the two peroxisomal acyl-CoA oxidases, that is, straight-chain acyl-CoA
- term:
    id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  evidence_type: IMP
  original_reference_id: PMID:18536048
  qualifier: involved_in
  review:
    summary: >-
      Correct core process, supported by the loss-of-function patient phenotype
      (straight-chain acyl-CoA oxidase deficiency with VLCFA accumulation).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:18536048
      supporting_text: >-
        one of the two peroxisomal acyl-CoA oxidases, that is, straight-chain acyl-CoA
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18281296
  qualifier: enables
  review:
    summary: >-
      Records a physical interaction with the peroxisomal Lon protease LONP2, which
      processes/activates AOX during peroxisomal import. The interaction itself is
      informative, but the bare 'protein binding' molecular-function term is
      uninformative and should not be treated as a core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      'protein binding' (GO:0005515) is an uninformative MF term; the underlying
      LONP2 interaction is a processing/import relationship, not an autonomous molecular
      function of ACOX1.
- term:
    id: GO:0003997
    label: acyl-CoA oxidase activity
  evidence_type: IMP
  original_reference_id: PMID:7876265
  qualifier: enables
  review:
    summary: >-
      Core molecular function. Recombinant human ACOX was purified and shown to be a
      catalytically active palmitoyl-CoA oxidase oxidizing straight-chain acyl-CoAs.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:7876265
      supporting_text: >-
        The palmitoyl-CoA oxidase (ACOX) oxidizes the CoA esters of straight chain fatty
        acids and prostaglandins and donates electrons directly to molecular oxygen
- term:
    id: GO:0003997
    label: acyl-CoA oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:8117268
  qualifier: enables
  review:
    summary: >-
      Core molecular function. Cloned human peroxisomal acyl-CoA oxidase was expressed and
      shown to be catalytically active.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8117268
      supporting_text: the expressed AOX was catalytically active
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:7876265
  qualifier: located_in
  review:
    summary: >-
      Correct core location. ACOX1 is the peroxisomal palmitoyl-CoA oxidase; peroxisomal
      localization is well established across studies.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
      supporting_text: Peroxisome {ECO:0000269|PubMed:32169171}.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:8117268
  qualifier: located_in
  review:
    summary: >-
      Correct core location. The cloned AOX carries the C-terminal SKL peroxisome-targeting
      signal and requires functional peroxisomes for accumulation (reduced in Zellweger
      fibroblasts).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:8117268
      supporting_text: known as a minimal peroxisome-targeting signal
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: IMP
  original_reference_id: PMID:7876265
  qualifier: involved_in
  review:
    summary: >-
      Misleading for peroxisomal beta-oxidation. Peroxisomal beta-oxidation is a
      degradative, chain-shortening, H2O2-generating process whose products are exported
      to the ER or mitochondria; unlike mitochondrial beta-oxidation it is not a primary
      energy-yielding pathway. This ancestor term over-states the metabolic role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Peroxisomal beta-oxidation does not generate cellular energy directly; the enzyme's
      role is degradative chain-shortening with H2O2 production.
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:8117268
  qualifier: involved_in
  review:
    summary: >-
      Correct but far too general. The demonstrated activity is fatty acid beta-oxidation;
      replace with the specific process term.
    action: MODIFY
    proposed_replacement_terms:
    - id: GO:0006635
      label: fatty acid beta-oxidation
    supported_by:
    - reference_id: PMID:8117268
      supporting_text: the expressed AOX was catalytically active
- term:
    id: GO:0006693
    label: prostaglandin metabolic process
  evidence_type: IMP
  original_reference_id: PMID:7876265
  qualifier: involved_in
  review:
    summary: >-
      ACOX1 oxidizes the CoA esters of prostaglandins (eicosanoids), so a role in
      prostaglandin metabolism is supported. However this is a secondary/minor activity
      relative to the core straight-chain VLCFA beta-oxidation function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Prostaglandin (eicosanoid-CoA) oxidation is a real but ancillary substrate range,
      not the core evolved function of the enzyme.
    supported_by:
    - reference_id: PMID:7876265
      supporting_text: >-
        oxidizes the CoA esters of straight chain fatty acids and prostaglandins
- term:
    id: GO:0019395
    label: fatty acid oxidation
  evidence_type: IMP
  original_reference_id: PMID:7876265
  qualifier: involved_in
  review:
    summary: >-
      Correct. ACOX1 performs the oxidase step of peroxisomal fatty acid oxidation; the
      more specific beta-oxidation terms are also annotated.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:7876265
      supporting_text: >-
        oxidizes the CoA esters of straight chain fatty acids and prostaglandins and
core_functions:
- description: >-
    FAD-dependent straight-chain acyl-CoA oxidase that catalyzes the first, rate-limiting
    and committed step of peroxisomal fatty-acid beta-oxidation: it dehydrogenates a
    2,3-saturated fatty acyl-CoA to the corresponding (2E)-enoyl-CoA and transfers the
    electrons directly to molecular oxygen, producing H2O2. Acts as a homodimer in the
    peroxisomal matrix.
  molecular_function:
    id: GO:0003997
    label: acyl-CoA oxidase activity
  directly_involved_in:
  - id: GO:0033540
    label: fatty acid beta-oxidation using acyl-CoA oxidase
  - id: GO:0140493
    label: very long-chain fatty acid beta-oxidation
  - id: GO:0050665
    label: hydrogen peroxide biosynthetic process
  locations:
  - id: GO:0005782
    label: peroxisomal matrix
  - id: GO:0005777
    label: peroxisome
  supported_by:
  - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
    supporting_text: >-
      Involved in the initial and rate-limiting step of peroxisomal
  - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
    supporting_text: >-
      donates electrons directly to molecular oxygen
  - reference_id: PMID:7876265
    supporting_text: >-
      oxidizes the CoA esters of straight chain fatty acids and prostaglandins and
- description: >-
    Binds FAD as its redox cofactor, required for the acyl-CoA oxidase reaction in which
    the reduced flavin is reoxidized by molecular oxygen.
  molecular_function:
    id: GO:0071949
    label: FAD binding
  locations:
  - id: GO:0005782
    label: peroxisomal matrix
  supported_by:
  - reference_id: file:human/ACOX1/ACOX1-uniprot.txt
    supporting_text: Name=FAD; Xref=ChEBI:CHEBI:57692;
- description: >-
    Assembles into a catalytically relevant homodimer, as established by the ACOX1
    crystal structure and by co-immunoprecipitation.
  molecular_function:
    id: GO:0042803
    label: protein homodimerization activity
  locations:
  - id: GO:0005782
    label: peroxisomal matrix
  supported_by:
  - reference_id: PMID:32169171
    supporting_text: >-
      The crystal structure of ACOX1 revealed that this enzyme acts as a homodimer bound
      to Flavin adenine dinucleotide (FAD)
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID: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: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Supports peroxisomal localization of ACOX1 via marker-protein detection in testis;
      contextual, not central to core function.
- id: PMID:18281296
  title: Contribution of peroxisome-specific isoform of Lon protease in sorting PTS1
    proteins to peroxisomes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Establishes the LONP2 (pLon)-AOX interaction and pLon-dependent processing/activation
      of AOX during peroxisomal import; source of the GO:0005515 IPI annotation.
- id: PMID:18536048
  title: 'Peroxisomal acyl-CoA-oxidase deficiency: two new cases.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Two ACOX1-deficiency patients with abnormal plasma VLCFAs and biallelic ACOX1
      mutations; supports acyl-CoA oxidase activity and VLCFA metabolism.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput NK-cell membrane proteome; ACOX1 appears as a non-specific hit.
      Source of the over-annotated GO:0016020 membrane annotation.
- id: PMID:23209302
  title: KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      Paper characterizes the Radil PDZ domain and its KIF14 ligand; the cached full text
      does not establish an ACOX1 PDZ-binding function. The GO:0030165 IDA annotation to
      ACOX1 is not verifiable from this reference (marked UNDECIDED rather than removed as
      it is an experimental annotation).
- id: PMID:32169171
  title: Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different
    Mechanisms.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available; establishes ACOX1 as first/rate-limiting VLCFA beta-oxidation
      enzyme and H2O2 producer, homodimer (crystal structure + co-IP), peroxisomal
      localization, and the N237S gain-of-function toxic-homodimer mechanism (Mitchell
      syndrome).
- id: PMID:7876265
  title: Overexpression and characterization of the human peroxisomal acyl-CoA oxidase
    in insect cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Purified recombinant human ACOX; establishes straight-chain/prostaglandin substrate
      specificity, direct electron transfer to O2 with H2O2 production, C12-18 optimum,
      and A/B/C chain processing.
- id: PMID:8117268
  title: Molecular cloning and functional expression of a human peroxisomal acyl-coenzyme
    A oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning and functional expression of human AOX; catalytically active, carries the
      C-terminal SKL PTS1 signal, peroxisome-dependent accumulation.
- id: PMID:8943006
  title: 'Molecular characterization of the human peroxisomal branched-chain acyl-CoA
    oxidase: cDNA cloning, chromosomal assignment, tissue distribution, and evidence
    for the absence of the protein in Zellweger syndrome.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Primarily characterizes the branched-chain oxidase (ACOX2) but documents the
      two-oxidase division in human liver peroxisomes and confirms ACOX1 (palmitoyl-CoA
      oxidase) oxidizes very-long straight-chain fatty acids and eicosanoids.
- id: file:human/ACOX1/ACOX1-uniprot.txt
  title: UniProtKB Q15067 (ACOX1_HUMAN) record
  findings: []
- id: Reactome:R-HSA-1989749
  title: Expression of ACOX1
  findings: []
- id: Reactome:R-HSA-2066787
  title: Oxidation of tetracosapentaenoyl-CoA to delta2-tetracosaheptaenoyl-CoA
  findings: []
- id: Reactome:R-HSA-390256
  title: ACOX1 oxidizes C26:0 CoA
  findings: []
- id: Reactome:R-HSA-9033235
  title: Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-9033236
  title: PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation
    Module)
  findings: []