id: P28288
gene_symbol: ABCD3
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ABCD3 (PMP70) is a peroxisomal ABC half-transporter that homodimerizes to form an active
  ATP-dependent transporter catalyzing import of fatty acid substrates into peroxisomes for beta-oxidation.
  It has broad substrate specificity, preferring hydrophilic substrates including long-chain unsaturated
  fatty acids, branched-chain fatty acids (pristanic acid), dicarboxylic acids, and bile acid CoA-esters.
  ABCD3 possesses intrinsic fatty acyl-CoA thioesterase activity and ATPase activity. Loss of ABCD3 causes
  congenital bile acid synthesis defect type 5 (CBAS5), characterized by accumulation of C27-bile acid
  intermediates. Recent cryo-EM structures reveal an alternating-access transport mechanism with substrate-induced
  NBD dimerization driving conformational changes from inward-open to outward-open states.
alternative_products:
- name: '1'
  id: P28288-1
- name: '2'
  id: P28288-2
  sequence_note: VSP_031189
- name: '3'
  id: P28288-3
  sequence_note: VSP_031187, VSP_031188
existing_annotations:
- term:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 is an established ATP-dependent peroxisomal membrane transporter. IBA annotation is
      phylogenetically sound and well-supported by direct experimental data from proteoliposome reconstitution
      studies [PMID:29397936] and yeast complementation assays [PMID:24333844].
    action: ACCEPT
    reason: Core molecular function of ABCD3, supported by multiple lines of experimental evidence including
      ATPase activity measurements and substrate transport assays.
    supported_by:
    - reference_id: PMID:29397936
      supporting_text: ABCD1-4 displayed stable ATPase activity, which was inhibited by AlF3
    - reference_id: PMID:24333844
      supporting_text: the phenotype of the pxa1/pxa2Delta yeast mutant, i.e. impaired oxidation of oleic
        acid, cannot only be partially rescued by HsABCD1, HsABCD2, but also by HsABCD3
- term:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 transports long-chain fatty acids across the peroxisomal membrane. Demonstrated by
      yeast complementation showing rescue of fatty acid oxidation defects [PMID:24333844] and supported
      by loss-of-function studies in knockout mice [PMID:34564857].
    action: ACCEPT
    reason: Core function. IBA annotation is well-supported by IMP evidence from van Roermund et al. showing
      ABCD3 can partially rescue oleic acid oxidation in yeast mutants.
    supported_by:
    - reference_id: PMID:24333844
      supporting_text: most hydrophilic substrates like long-chain unsaturated-, long branched-chain-
        and long-chain dicarboxylic fatty acids by HsABCD3
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 is a well-established peroxisomal membrane protein, demonstrated by immunofluorescence
      and FRET microscopy in multiple studies [PMID:17609205, PMID:17761678, PMID:10704444].
    action: ACCEPT
    reason: 'Core localization. Extensively validated by multiple experimental methods including immunofluorescence,
      FRET, and cryo-EM structures (PDB: 8Z0F, 8Z9X).'
    supported_by:
    - reference_id: PMID:17609205
      supporting_text: ALDP and PMP70 form homodimers as well as ALDP/PMP70 heterodimers
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 facilitates import of fatty acid substrates into peroxisomes for beta-oxidation. Supported
      by yeast complementation studies [PMID:24333844] and overexpression rescue of VLCFA beta-oxidation
      defects [PMID:9425230].
    action: ACCEPT
    reason: Core biological process. ABCD3 imports substrates destined for peroxisomal beta-oxidation.
      IBA is phylogenetically sound and experimentally validated.
    supported_by:
    - reference_id: PMID:24333844
      supporting_text: the phenotype of the pxa1/pxa2Delta yeast mutant, i.e. impaired oxidation of oleic
        acid, cannot only be partially rescued by HsABCD1, HsABCD2, but also by HsABCD3
    - reference_id: PMID:9425230
      supporting_text: Expression of either ALDP or PMP70 restores VLCFA beta-oxidation in X-ALD fibroblasts,
        indicating overlapping functions
- term:
    id: GO:0015910
    label: long-chain fatty acid import into peroxisome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 imports long-chain fatty acids into peroxisomes as CoA esters. Supported by yeast complementation
      [PMID:24333844] and ABCD3-deficient patient data [PMID:25168382].
    action: ACCEPT
    reason: Core function of ABCD3. Phylogenetically conserved and experimentally validated.
    supported_by:
    - reference_id: PMID:24333844
      supporting_text: All these fatty acids are most likely transported as CoA esters
- term:
    id: GO:0042760
    label: very long-chain fatty acid catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 contributes to VLCFA catabolism by importing substrates for peroxisomal beta-oxidation.
      Supported by IGI evidence from ABCD1/ABCD3 co-expression studies [PMID:9425230], though ABCD1 is
      the primary VLCFA transporter.
    action: KEEP_AS_NON_CORE
    reason: ABCD3 contributes to VLCFA catabolism but is not the primary transporter for VLCFAs. ABCD1
      preferentially handles the most hydrophobic VLCFAs (C24:0, C26:0) [PMID:24333844]. ABCD3 prefers
      more hydrophilic substrates. The Ferdinandusse et al. patient showed normal C26:0 beta-oxidation
      despite ABCD3 deficiency [PMID:25168382].
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic
        acid was reduced
    - reference_id: PMID:24333844
      supporting_text: most hydrophobic C24:0 and C26:0 fatty acids are preferentially transported by
        HsABCD1
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 binds ATP via its nucleotide binding fold. Directly demonstrated by purified NBF studies
      with KM of 8.2 uM for ATP [PMID:11248239].
    action: ACCEPT
    reason: Core function, essential for transport activity. Phylogenetically conserved ABC transporter
      feature with direct experimental validation.
    supported_by:
    - reference_id: PMID:11248239
      supporting_text: Both proteins act as an ATP specific binding subunit releasing ADP after ATP hydrolysis
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ABCD3 overexpression can rescue peroxisome biogenesis defects in PEX2-deficient cells [PMID:9425230,
      PMID:9765053]. This likely reflects its role as a major peroxisomal membrane component rather than
      a direct organizer of peroxisome biogenesis.
    action: KEEP_AS_NON_CORE
    reason: Not a core function. The effect on peroxisome organization is indirect, reflecting ABCD3's
      abundance in the peroxisomal membrane rather than a direct role in peroxisome biogenesis.
    supported_by:
    - reference_id: PMID:9425230
      supporting_text: Their expression also restores peroxisome biogenesis in cells that are deficient
        in the peroxisomal membrane protein Pex2p
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat ortholog. ABCD3 is overwhelmingly established as a peroxisomal membrane
      protein. The N-terminal 80aa segment of PMP70, when expressed alone, can target to the outer mitochondrial
      membrane [PMID:20007743], but full-length PMP70 localizes exclusively to peroxisomes. This IEA annotation
      is misleading.
    action: REMOVE
    reason: ABCD3 is a peroxisomal protein. While an isolated N-terminal fragment can mis-target to mitochondria
      [PMID:20007743], this is an artifact of truncation, not physiological localization. No full-length
      ABCD3 has been demonstrated in mitochondria.
    supported_by:
    - reference_id: PMID:20007743
      supporting_text: When the N80-segment was fused to EGFP, the fusion protein was targeted to the
        outer mitochondrial membrane... The full-length PMP70 molecule was clearly located in the ER in
        the absence of the N80-segment
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ABCD3 imports C27-bile acid intermediates into peroxisomes for side-chain shortening, a critical
      step in bile acid biosynthesis. Loss of ABCD3 causes CBAS5 with accumulation of C27-bile acid intermediates
      [PMID:25168382].
    action: ACCEPT
    reason: Well-supported by patient data and knockout mouse studies. ABCD3 transports bile acid CoA-esters
      (DHCA-CoA, THCA-CoA) into peroxisomes for conversion to mature C24 bile acids.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids
        into the peroxisome and that this is a crucial step in bile acid biosynthesis
- term:
    id: GO:0006869
    label: lipid transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ABCD3 transports lipid substrates (fatty acids, bile acid intermediates) across the peroxisomal
      membrane. This is a correct but very general annotation.
    action: ACCEPT
    reason: Correct but general. More specific terms (GO:0015910, GO:0015721) are also annotated and provide
      more precise functional description. Acceptable as a broader IEA annotation.
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: IEA transfer from rat ortholog. In rat, PMP70 expression may be upregulated by peroxisome
      proliferators (xenobiotics), but this is a transcriptional response, not a direct function of the
      ABCD3 protein itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: Transcriptional upregulation by xenobiotics reflects regulatory biology, not a direct function
      of the ABCD3 protein. This annotation conflates gene regulation with protein function.
- term:
    id: GO:0015721
    label: bile acid and bile salt transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ABCD3 transports C27-bile acid CoA-ester intermediates (DHCA-CoA, THCA-CoA) into peroxisomes.
      Loss of ABCD3 leads to accumulation of these intermediates [PMID:25168382]. Cryo-EM studies confirm
      bile acid intermediates as ABCD3-specific substrates [PMID:39223112].
    action: ACCEPT
    reason: Well-supported by patient genetics, knockout mice, and structural studies. DHCA-CoA and THCA-CoA
      are ABCD3-specific substrates per cryo-EM data.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids
        into the peroxisome
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ABCD3 forms homodimers, demonstrated by FRET microscopy in living cells [PMID:17609205].
      However, the more specific term GO:0042803 (protein homodimerization activity) is already annotated
      with IDA evidence. This IEA annotation is redundant and less informative.
    action: MODIFY
    reason: The more specific GO:0042803 (protein homodimerization activity) is already annotated with
      direct experimental evidence (IDA, PMID:17609205). This IEA term is less precise.
    proposed_replacement_terms:
    - id: GO:0042803
      label: protein homodimerization activity
- term:
    id: GO:1903512
    label: phytanic acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: ABCD3 imports branched-chain fatty acids including pristanic acid (the alpha-oxidation product
      of phytanic acid) into peroxisomes. Abcd3 knockout mice accumulate phytanic acid after phytol loading
      [PMID:25168382]. The ABCD3-deficient patient showed reduced pristanic acid beta-oxidation [PMID:25168382].
    action: ACCEPT
    reason: Supported by knockout mouse and patient data showing impaired branched-chain fatty acid metabolism
      when ABCD3 is absent.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol
        loading
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10551832
  review:
    summary: Demonstrates heterodimerization of ABCD3 (PMP70) with ABCD1 (ALDP) by yeast two-hybrid and
      co-immunoprecipitation [PMID:10551832]. Per curation guidelines, 'protein binding' is uninformative;
      a more specific term should be used.
    action: MODIFY
    reason: The interaction with ABCD1 is well-established but 'protein binding' is uninformative. Should
      be annotated with a more specific term reflecting heterodimerization.
    proposed_replacement_terms:
    - id: GO:0046982
      label: protein heterodimerization activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10704444
  review:
    summary: Demonstrates interaction of ABCD3 with PEX19, which is required for targeting ABCD3 to peroxisomes
      [PMID:10704444]. PEX19 is a cytosolic chaperone/import receptor for class I peroxisomal membrane
      proteins, of which ABCD3 is a client.
    action: MODIFY
    reason: Specific interaction with PEX19 (a peroxisomal biogenesis chaperone/import receptor) is well-characterized
      but 'protein binding' is uninformative. PEX19 is a distinct protein (not ABCD3 itself), so homo-/heterodimerization
      terms are inappropriate. ABCD3 binds PEX19 as a client of this chaperone, so a chaperone-binding term
      is the more informative molecular function.
    proposed_replacement_terms:
    - id: GO:0051087
      label: protein-folding chaperone binding
    additional_reference_ids:
    - PMID:16344115
    - PMID:17761678
    supported_by:
    - reference_id: PMID:10704444
      supporting_text: PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic,
        and is required for peroxisome membrane synthesis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14709540
  review:
    summary: PEX19 acts as a cytosolic chaperone and import receptor for class 1 peroxisomal membrane
      proteins including ABCD3 [PMID:14709540]. Duplicates the PEX19 interaction from other entries.
    action: REMOVE
    reason: Uninformative 'protein binding' annotation. The PEX19 interaction is already captured by other
      annotations. Per curation guidelines, protein binding should be avoided.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21102411
  review:
    summary: Structural basis for PEX19/PEX3 docking [PMID:21102411]. ABCD3 is one of many PEX19 cargo
      proteins studied. Again, 'protein binding' is uninformative.
    action: REMOVE
    reason: Uninformative 'protein binding' annotation. The PEX19 interaction is well-covered by other
      annotations. Per curation guidelines, protein binding should be avoided.
- term:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: InterPro-based annotation from IPR005283 (fatty acid transporter). Correct and consistent
      with experimental evidence from yeast complementation [PMID:24333844].
    action: ACCEPT
    reason: Correct IEA annotation consistent with IBA and experimental annotations for same term.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Combined automated annotation. ATP binding is well-established for ABCD3 with IDA evidence
      [PMID:11248239, KM = 8.2 uM].
    action: ACCEPT
    reason: Consistent with experimentally validated annotations.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Combined automated annotation for peroxisomal localization. Well-supported by extensive experimental
      evidence.
    action: ACCEPT
    reason: Consistent with multiple IDA annotations for peroxisomal localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Combined automated annotation for peroxisomal membrane localization.
    action: ACCEPT
    reason: Consistent with extensive experimental evidence for peroxisomal membrane localization.
- term:
    id: GO:0015910
    label: long-chain fatty acid import into peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: InterPro-based annotation. Consistent with IMP evidence from yeast complementation [PMID:24333844].
    action: ACCEPT
    reason: Consistent with experimental annotations.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Generic membrane annotation from InterPro. Correct but very general; more specific peroxisomal
      membrane annotations exist.
    action: ACCEPT
    reason: Correct but very general. Acceptable as a broad IEA annotation alongside more specific peroxisomal
      membrane annotations.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: InterPro-based annotation. Consistent with IDA evidence from NBF studies [PMID:11248239]
      and proteoliposome reconstitution [PMID:29397936].
    action: ACCEPT
    reason: Consistent with experimental annotations.
- term:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: InterPro-based annotation. Consistent with IDA evidence from proteoliposome studies [PMID:29397936].
    action: ACCEPT
    reason: Consistent with IDA annotation for same term.
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Generic transmembrane transport annotation. Correct but very general.
    action: ACCEPT
    reason: Correct but general. More specific transport process terms are also annotated.
- term:
    id: GO:0140359
    label: ABC-type transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: InterPro-based annotation reflecting ABC transporter domain architecture. ABCD3 is indeed
      a member of the ABCD family of ABC transporters.
    action: ACCEPT
    reason: Correct classification. ABCD3 belongs to the ABC transporter superfamily, ABCD family.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: HPA immunofluorescence data confirming peroxisomal localization of ABCD3.
    action: ACCEPT
    reason: Core localization, independently validated by multiple methods.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-382575
  review:
    summary: 'Reactome pathway: ABCD1-3 dimers transfer LCFAs from cytosol to peroxisomal matrix. Consistent
      with ABCD3 function.'
    action: ACCEPT
    reason: Consistent with established localization and function.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-382613
  review:
    summary: 'Reactome pathway: PEX19 docks ABCD3 to peroxisomal membrane.'
    action: ACCEPT
    reason: Consistent with PEX19-mediated targeting of ABCD3 to peroxisomes.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    summary: 'Reactome pathway: PEX3:PEX19:class I PMP dissociates. ABCD3 is a class I PMP.'
    action: ACCEPT
    reason: Consistent with peroxisomal membrane protein import pathway.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-382613
  review:
    summary: 'Reactome: PEX19 docks ABCD3 to peroxisomal membrane, implying ABCD3 transits through cytosol
      during biogenesis. ABCD3 is synthesized on free ribosomes and targeted posttranslationally [PMID:17761678].'
    action: KEEP_AS_NON_CORE
    reason: ABCD3 passes through the cytosol during posttranslational targeting but its steady-state localization
      is peroxisomal membrane. Cytosol is a transient location during biogenesis, not the functional site.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603775
  review:
    summary: 'Reactome: PEX3:PEX19:class I PMP complex dissociation. Transient cytosolic location during
      import pathway.'
    action: KEEP_AS_NON_CORE
    reason: Transient localization during biogenesis, not functional site.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603784
  review:
    summary: 'Reactome: PEX19:class I PMP binds PEX3. Part of peroxisomal membrane protein import.'
    action: KEEP_AS_NON_CORE
    reason: Transient localization during biogenesis.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9603804
  review:
    summary: 'Reactome: PEX19 binds class I peroxisomal membrane proteins in cytosol.'
    action: KEEP_AS_NON_CORE
    reason: Transient localization during biogenesis.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: EXP
  original_reference_id: PMID:10704444
  review:
    summary: PEX19 binds ABCD3 and is required for its localization to peroxisomal membrane [PMID:10704444].
      Subcellular fractionation and immunofluorescence confirm peroxisomal membrane localization.
    action: ACCEPT
    reason: Core localization with direct experimental evidence from subcellular fractionation and immunofluorescence.
    supported_by:
    - reference_id: PMID:10704444
      supporting_text: PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic,
        and is required for peroxisome membrane synthesis
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: EXP
  original_reference_id: PMID:16344115
  review:
    summary: PEX19 mediates targeting of PMP70 to peroxisomes [PMID:16344115]. Confirms peroxisomal membrane
      localization through PEX19 binding studies.
    action: ACCEPT
    reason: Core localization confirmed by PEX19 interaction and targeting studies.
    supported_by:
    - reference_id: PMID:16344115
      supporting_text: Role of Pex19p in the targeting of PMP70 to peroxisome
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: EXP
  original_reference_id: PMID:17761678
  review:
    summary: Hydrophobic regions adjacent to TMDs 1 and 5 are required for PMP70 targeting to peroxisomal
      membrane [PMID:17761678]. Mutagenesis of targeting signals (L21Q/L22Q/L23Q, I70N/L71Q, I307A/L308A)
      abolishes peroxisomal localization.
    action: ACCEPT
    reason: Core localization. Detailed targeting signal mapping confirms peroxisomal membrane as the
      destination.
    supported_by:
    - reference_id: PMID:17761678
      supporting_text: PMP70 possesses two distinct targeting signals, and hydrophobic regions adjacent
        to the first TMD of each region are important for targeting
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: EXP
  original_reference_id: PMID:24333844
  review:
    summary: Subcellular fractionation and functional studies in yeast confirm ABCD3 localizes to peroxisomal
      membrane [PMID:24333844].
    action: ACCEPT
    reason: Core localization confirmed in context of substrate transport studies.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: EXP
  original_reference_id: PMID:29397936
  review:
    summary: ABCD3 reconstituted into proteoliposomes for functional studies, confirming membrane protein
      nature [PMID:29397936].
    action: ACCEPT
    reason: Core localization confirmed in proteoliposome reconstitution.
- term:
    id: GO:0052817
    label: very long-chain fatty acyl-CoA hydrolase activity
  evidence_type: EXP
  original_reference_id: PMID:29397936
  review:
    summary: ABCD3 reconstituted in proteoliposomes displays acyl-CoA thioesterase activity, cleaving
      fatty acyl-CoA into free fatty acid and CoA [PMID:29397936]. This activity is shared by ABCD1-4.
    action: ACCEPT
    reason: Directly demonstrated in purified reconstituted system. The thioesterase activity is proposed
      to hydrolyze fatty acyl-CoAs prior to ATP-dependent transport.
    supported_by:
    - reference_id: PMID:29397936
      supporting_text: ABCD1-4 were found to possess an equal levels of acyl-CoA thioesterase activity
- term:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:24333844
  review:
    summary: Expression of human ABCD3 in pxa1/pxa2-delta yeast mutants partially rescues fatty acid oxidation,
      demonstrating transporter function [PMID:24333844]. ABCD3 preferentially transports hydrophilic
      substrates including long-chain unsaturated fatty acids.
    action: ACCEPT
    reason: Core function demonstrated by yeast complementation assay. Key evidence for substrate specificity
      of ABCD3.
    supported_by:
    - reference_id: PMID:24333844
      supporting_text: most hydrophilic substrates like long-chain unsaturated-, long branched-chain-
        and long-chain dicarboxylic fatty acids by HsABCD3
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS from mouse ortholog P55096. Well-supported by ABCD3-deficient patient showing accumulation
      of C27-bile acid intermediates [PMID:25168382] and Abcd3 KO mice with reduced C24 bile acids and
      increased C27 intermediates [PMID:25168382, PMID:34564857].
    action: ACCEPT
    reason: Core function. ABCD3 imports bile acid CoA-ester intermediates into peroxisomes for side-chain
      shortening, an essential step in bile acid biosynthesis.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids
        into the peroxisome and that this is a crucial step in bile acid biosynthesis
- term:
    id: GO:0015721
    label: bile acid and bile salt transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS from mouse ortholog. ABCD3 transports bile acid CoA-ester intermediates (DHCA-CoA, THCA-CoA)
      into peroxisomes. Supported by human genetics [PMID:25168382] and cryo-EM structural data showing
      these are ABCD3-specific substrates [PMID:39223112].
    action: ACCEPT
    reason: Core function. DHCA-CoA and THCA-CoA are ABCD3-specific substrates per cryo-EM data. In vivo
      loss-of-function confirms bile acid transport role.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: both in the patient and in Abcd3-/- mice, there was evidence of a bile acid biosynthesis
        defect
- term:
    id: GO:0015910
    label: long-chain fatty acid import into peroxisome
  evidence_type: IMP
  original_reference_id: PMID:24333844
  review:
    summary: ABCD3 expression in pxa1/pxa2-delta yeast rescues fatty acid oxidation, demonstrating import
      of long-chain fatty acids into peroxisomes [PMID:24333844].
    action: ACCEPT
    reason: Core function with direct IMP evidence.
    supported_by:
    - reference_id: PMID:24333844
      supporting_text: the phenotype of the pxa1/pxa2Delta yeast mutant, i.e. impaired oxidation of oleic
        acid, cannot only be partially rescued by HsABCD1, HsABCD2, but also by HsABCD3
- term:
    id: GO:1903512
    label: phytanic acid metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS from mouse ortholog. ABCD3 imports pristanic acid (and by extension contributes to phytanic
      acid metabolism) into peroxisomes. Abcd3 KO mice accumulate phytanic acid [PMID:25168382].
    action: ACCEPT
    reason: Well-supported by knockout mouse data and patient studies showing reduced pristanic acid beta-oxidation.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol
        loading
- term:
    id: GO:0000038
    label: very long-chain fatty acid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:29397936
  review:
    summary: ABCD3 reconstituted in proteoliposomes demonstrates thioesterase and ATPase activities with
      fatty acyl-CoA substrates [PMID:29397936], contributing to VLCFA metabolism.
    action: KEEP_AS_NON_CORE
    reason: ABCD3 can process VLCFAs but this is not its primary substrate preference. ABCD1 is the main
      VLCFA transporter. The ABCD3-deficient patient had normal C26:0 beta-oxidation [PMID:25168382],
      indicating ABCD3 is not essential for VLCFA catabolism.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: Peroxisomal beta-oxidation of C26:0 was normal
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:24333844
  review:
    summary: Subcellular fractionation confirms ABCD3 localization to peroxisomes [PMID:24333844].
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:11248239
  review:
    summary: Purified nucleotide binding fold (NBF) of PMP70 hydrolyzes ATP (KM = 8.2 uM). ATP-specific,
      no GTPase activity. Mutations G478R and S572I alter ATPase activity [PMID:11248239].
    action: ACCEPT
    reason: Core activity. Direct biochemical demonstration with purified protein.
    supported_by:
    - reference_id: PMID:11248239
      supporting_text: Both proteins act as an ATP specific binding subunit releasing ADP after ATP hydrolysis;
        they did not exhibit GTPase activity
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:29397936
  review:
    summary: ABCD3 reconstituted in proteoliposomes displays stable ATPase activity inhibited by AlF3
      [PMID:29397936], confirming the NBF study findings in a full-length protein context.
    action: ACCEPT
    reason: Core activity confirmed in full-length reconstituted protein.
    supported_by:
    - reference_id: PMID:29397936
      supporting_text: ABCD1-4 displayed stable ATPase activity, which was inhibited by AlF3
- term:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:29397936
  review:
    summary: Proteoliposome reconstitution demonstrates coupled ATPase-transport activity of ABCD3 [PMID:29397936].
      Cryo-EM structures capture the conformational cycle linking ATP hydrolysis to substrate translocation
      [PMID:39223112].
    action: ACCEPT
    reason: Core molecular function. Direct demonstration in reconstituted system with structural validation
      of the transport mechanism.
    supported_by:
    - reference_id: PMID:29397936
      supporting_text: ABCD1-3 are located on peroxisomal membrane and play an important role in the transportation
        of various fatty acid-CoA derivatives
- term:
    id: GO:0047617
    label: fatty acyl-CoA hydrolase activity
  evidence_type: IDA
  original_reference_id: PMID:29397936
  review:
    summary: ABCD3 possesses intrinsic acyl-CoA thioesterase activity demonstrated in proteoliposomes
      [PMID:29397936]. This activity may hydrolyze fatty acyl-CoAs to free fatty acids prior to transport,
      though the cryo-EM studies suggest intact CoA-esters may also be transported.
    action: ACCEPT
    reason: Directly demonstrated enzymatic activity. The biological significance (whether thioesterase
      activity is required for transport or is a side activity) remains under investigation, but the activity
      is real.
    supported_by:
    - reference_id: PMID:29397936
      supporting_text: ABCD1-4 were found to possess an equal levels of acyl-CoA thioesterase activity
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IDA
  original_reference_id: PMID:24333844
  review:
    summary: ABCD3 expression in yeast mutants restores fatty acid beta-oxidation, particularly for hydrophilic
      substrates [PMID:24333844]. Fatty acid oxidation measurements with various substrates reveal distinctive
      substrate preferences.
    action: ACCEPT
    reason: Core function supported by direct biochemical evidence.
    supported_by:
    - reference_id: PMID:24333844
      supporting_text: the phenotype of the pxa1/pxa2Delta yeast mutant, i.e. impaired oxidation of oleic
        acid, cannot only be partially rescued by HsABCD1, HsABCD2, but also by HsABCD3
- term:
    id: GO:0006633
    label: fatty acid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:25168382
  review:
    summary: This annotation is problematic. PMID:25168382 describes a bile acid biosynthesis defect in
      an ABCD3-deficient patient, not a fatty acid biosynthesis defect. The patient showed accumulation
      of C27-bile acid intermediates. ABCD3 does not synthesize fatty acids; it imports them for degradation.
      The correct annotation should be GO:0006699 (bile acid biosynthetic process), which is already annotated
      separately.
    action: MODIFY
    reason: PMID:25168382 describes a bile acid biosynthesis defect, not fatty acid biosynthesis. ABCD3
      imports substrates for beta-oxidation (catabolism), not biosynthesis. The KO mice showed altered
      lipogenesis [PMID:34564857] as a secondary metabolic effect, but this is not a direct function of
      ABCD3. The correct term for the primary finding is bile acid biosynthetic process.
    proposed_replacement_terms:
    - id: GO:0006699
      label: bile acid biosynthetic process
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: High-throughput proteomics identification of ABCD3 in NK cell membrane fractions [PMID:19946888].
      Generic membrane annotation.
    action: ACCEPT
    reason: Correct but very general. ABCD3 is indeed a membrane protein. More specific peroxisomal membrane
      annotations provide better functional context.
- term:
    id: GO:0005782
    label: peroxisomal matrix
  evidence_type: IDA
  original_reference_id: PMID:9765053
  review:
    summary: PMID:9765053 describes restoration of PEX2 peroxisome assembly defects by overexpression
      of PMP70. ABCD3 is a multi-pass transmembrane protein with its NBD domain extending into the cytosol.
      The annotation to peroxisomal matrix is problematic for a transmembrane protein, unless referring
      to the NBD domain facing the matrix side. However, cryo-EM structures show the NBDs are cytosolic
      [PMID:39223112].
    action: REMOVE
    reason: ABCD3 is an integral membrane protein of the peroxisomal membrane with its NBD domain in the
      cytosol. It is not a peroxisomal matrix protein. The cryo-EM structures confirm the cytosolic orientation
      of the NBDs [PMID:39223112]. Peroxisomal matrix annotation is incorrect for this transmembrane protein.
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IMP
  original_reference_id: PMID:9765053
  review:
    summary: Overexpression of PMP70 restores peroxisome assembly in PEX2-deficient cells [PMID:9765053].
      This is an indirect effect of providing abundant peroxisomal membrane protein.
    action: KEEP_AS_NON_CORE
    reason: Not a direct function. The rescue of peroxisome assembly defects by PMP70 overexpression is
      an indirect compensatory effect, not evidence of a primary role in peroxisome organization.
    supported_by:
    - reference_id: PMID:9765053
      supporting_text: Restoration of PEX2 peroxisome assembly defects by overexpression of PMP70
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:17542813
  review:
    summary: Immunofluorescence study showing ABCD3 localizes to peroxisomes [PMID:17542813]. The paper
      primarily studies ABCD1/ALDP but confirms ABCD3 peroxisomal localization.
    action: ACCEPT
    reason: Core localization confirmed by immunofluorescence.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:20007743
  review:
    summary: Multiple targeting signals in the N-terminal portion of PMP70 direct it to peroxisomes [PMID:20007743].
      Confirms peroxisomal localization.
    action: ACCEPT
    reason: Core localization.
    supported_by:
    - reference_id: PMID:20007743
      supporting_text: Cooperation of the organelle-targeting signals enables PMP70 to correctly target
        to peroxisomal membranes
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:19479899
  review:
    summary: Pex3p-dependent peroxisomal biogenesis initiates in the ER of human fibroblasts [PMID:19479899].
      ABCD3 used as a peroxisomal marker.
    action: ACCEPT
    reason: Core localization; ABCD3 is routinely used as a peroxisomal marker.
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IGI
  original_reference_id: PMID:9425230
  review:
    summary: Expression of PMP70 restores VLCFA beta-oxidation in X-ALD (ABCD1-deficient) fibroblasts,
      demonstrating overlapping function between ABCD1 and ABCD3 in fatty acid beta-oxidation [PMID:9425230].
    action: ACCEPT
    reason: Core function. IGI evidence from complementation showing ABCD3 can substitute for ABCD1 in
      supporting VLCFA beta-oxidation.
    supported_by:
    - reference_id: PMID:9425230
      supporting_text: Expression of either ALDP or PMP70 restores VLCFA beta-oxidation in X-ALD fibroblasts,
        indicating overlapping functions
- term:
    id: GO:0007031
    label: peroxisome organization
  evidence_type: IDA
  original_reference_id: PMID:9425230
  review:
    summary: ABCD3 expression restores peroxisome biogenesis in PEX2-deficient cells [PMID:9425230]. Indirect
      effect of providing peroxisomal membrane components.
    action: KEEP_AS_NON_CORE
    reason: Not a direct function. Same indirect rescue as PMID:9765053.
    supported_by:
    - reference_id: PMID:9425230
      supporting_text: Their expression also restores peroxisome biogenesis in cells that are deficient
        in the peroxisomal membrane protein Pex2p
- term:
    id: GO:0042760
    label: very long-chain fatty acid catabolic process
  evidence_type: IGI
  original_reference_id: PMID:9425230
  review:
    summary: ABCD3 expression restores VLCFA beta-oxidation in ABCD1-deficient cells [PMID:9425230].
    action: KEEP_AS_NON_CORE
    reason: ABCD3 can contribute to VLCFA catabolism but it is not the primary VLCFA transporter. ABCD1
      handles C24:0/C26:0 preferentially [PMID:24333844]. The ABCD3-deficient patient had normal C26:0
      beta-oxidation [PMID:25168382].
    supported_by:
    - reference_id: PMID:9425230
      supporting_text: Expression of either ALDP or PMP70 restores VLCFA beta-oxidation in X-ALD fibroblasts,
        indicating overlapping functions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10777694
  review:
    summary: Interaction of ABCD3 with PEX19 demonstrated by various binding assays [PMID:10777694]. Per
      curation guidelines, 'protein binding' is uninformative.
    action: REMOVE
    reason: Uninformative. The PEX19 interaction is functionally relevant for peroxisomal targeting but
      'protein binding' does not capture this. The interaction is already reflected in the peroxisomal
      membrane localization annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17609205
  review:
    summary: FRET microscopy demonstrating ABCD3 homo- and heterodimerization with ABCD1 in living cells
      [PMID:17609205]. The specific homodimerization function is already annotated as GO:0042803 (protein
      homodimerization activity) with IDA evidence from the same paper.
    action: REMOVE
    reason: Uninformative. The functional interaction is better captured by GO:0042803 (protein homodimerization
      activity) already annotated from this same reference.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9425230
  review:
    summary: ABCD3 localizes to peroxisomes [PMID:9425230].
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0005778
    label: peroxisomal membrane
  evidence_type: IDA
  original_reference_id: PMID:17609205
  review:
    summary: FRET microscopy in living cells confirms ABCD3 localization to peroxisomal membrane where
      it forms homodimers [PMID:17609205].
    action: ACCEPT
    reason: Core localization with in vivo FRET confirmation.
    supported_by:
    - reference_id: PMID:17609205
      supporting_text: ALDP and PMP70 form homodimers as well as ALDP/PMP70 heterodimers where ALDP homodimers
        predominate
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:17609205
  review:
    summary: FRET microscopy in living cells demonstrates ABCD3 homodimerization [PMID:17609205]. Dimerization
      is necessary for functional transporter activity. Also supported by cryo-EM structures showing homodimeric
      assembly [PMID:39223112, PMID:40501884].
    action: ACCEPT
    reason: Core function. Half-transporter dimerization is essential for ABC transporter function. Structural
      studies confirm the homodimeric arrangement.
    supported_by:
    - reference_id: PMID:17609205
      supporting_text: We demonstrate in vivo that ALDP and PMP70 form homodimers as well as ALDP/PMP70
        heterodimers
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16344115
  review:
    summary: PEX19 interaction with ABCD3 for peroxisomal targeting [PMID:16344115].
    action: REMOVE
    reason: Uninformative 'protein binding'. The PEX19 interaction is already reflected in peroxisomal
      membrane localization annotations.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:16344115
  review:
    summary: ABCD3 localization to peroxisomes confirmed in PEX19 targeting studies [PMID:16344115].
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11453642
  review:
    summary: Targeting elements in the N-terminal part of PMP70 [PMID:11453642]. PEX19 interaction.
    action: REMOVE
    reason: Uninformative 'protein binding'. PEX19 interaction covered elsewhere.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:11248239
  review:
    summary: Direct measurement of ATP binding by purified NBF of PMP70 with KM = 8.2 uM [PMID:11248239].
      ATP-specific, no GTP binding.
    action: ACCEPT
    reason: Core function with direct biochemical evidence.
    supported_by:
    - reference_id: PMID:11248239
      supporting_text: Both proteins act as an ATP specific binding subunit releasing ADP after ATP hydrolysis
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:11453642
  review:
    summary: ABCD3 localizes to peroxisomes [PMID:11453642].
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11590176
  review:
    summary: Two different targeting signals direct human PMP22 to peroxisomes [PMID:11590176]. ABCD3
      interaction context. Uninformative term.
    action: REMOVE
    reason: Uninformative 'protein binding'.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11883941
  review:
    summary: PEX19 splice variants and their functions in peroxisomal assembly [PMID:11883941]. ABCD3
      as PEX19 cargo. Uninformative term.
    action: REMOVE
    reason: Uninformative 'protein binding'. PEX19 interaction covered by other annotations.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:9922452
  review:
    summary: Peroxisome synthesis in the absence of preexisting peroxisomes [PMID:9922452]. ABCD3 used
      as peroxisomal marker.
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IDA
  original_reference_id: PMID:10704444
  review:
    summary: ABCD3 localizes to peroxisomes, requires PEX19 for targeting [PMID:10704444].
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0015125
    label: bile acid transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:25168382
  review:
    summary: ABCD3 specifically transports C27-bile acid CoA-ester intermediates (DHCA-CoA, THCA-CoA)
      across the peroxisomal membrane. Loss of ABCD3 causes accumulation of these intermediates in patient
      plasma [PMID:25168382] and in Abcd3 KO mice [PMID:25168382, PMID:34564857]. Cryo-EM structural data
      identifies these bile acid intermediates as ABCD3-specific substrates [PMID:39223112]. The existing
      annotations capture the bile acid transport process (GO:0015721) but no molecular function term for
      bile acid transporter activity is present.
    action: NEW
    reason: ABCD3 catalyzes transmembrane transport of bile acid CoA-esters across the peroxisomal membrane.
      The existing process annotation GO:0015721 (bile acid and bile salt transport) covers the broader
      biological process. This molecular function term captures the direct transporter activity and is supported
      by patient genetics, KO mice, and cryo-EM substrate-binding data.
    supported_by:
    - reference_id: PMID:25168382
      supporting_text: ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids
        into the peroxisome
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:17609205
  review:
    summary: ABCD3 forms heterodimers with ABCD1 and ABCD2, demonstrated by FRET microscopy in living
      cells [PMID:17609205] and by yeast two-hybrid and co-immunoprecipitation [PMID:10551832]. This is
      a more informative annotation than the generic 'protein binding' currently annotated for the ABCD1/ABCD3
      interaction.
    action: NEW
    reason: Replaces uninformative 'protein binding' annotations. ABCD3 heterodimerization with ABCD1
      is well-established and functionally relevant, as it creates transporters with potentially different
      substrate preferences.
    supported_by:
    - reference_id: PMID:17609205
      supporting_text: We demonstrate in vivo that ALDP and PMP70 form homodimers as well as ALDP/PMP70
        heterodimers
    - reference_id: PMID:10551832
      supporting_text: Co-immunoprecipitation demonstrated the homodimerization of ALDP, the heterodimerization
        of ALDP with PMP70
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9425230
  title: Suppression of peroxisomal membrane protein defects by peroxisomal ATP binding cassette (ABC)
    proteins.
  findings:
  - statement: Expression of PMP70 restores VLCFA beta-oxidation in X-ALD fibroblasts
  - statement: PMP70 and ALDP expression restores peroxisome biogenesis in PEX2-deficient cells
  - statement: Indicates overlapping functions between peroxisomal ABC transporters
- id: PMID:9765053
  title: Restoration of PEX2 peroxisome assembly defects by overexpression of PMP70.
  findings:
  - statement: PMP70 overexpression rescues PEX2-deficient peroxisome assembly
- id: PMID:9922452
  title: Peroxisome synthesis in the absence of preexisting peroxisomes.
  findings:
  - statement: ABCD3 used as peroxisomal marker to track de novo peroxisome synthesis
- id: PMID:10551832
  title: Homo- and heterodimerization of peroxisomal ATP-binding cassette half-transporters.
  findings:
  - statement: ABCD3 (PMP70) homo- and heterodimerizes with ABCD1 (ALDP) and ABCD2 (ALDRP)
  - statement: Demonstrated by yeast two-hybrid and co-immunoprecipitation
  - statement: C-terminal halves mediate dimerization
- id: PMID:10704444
  title: PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required
    for peroxisome membrane synthesis.
  findings:
  - statement: PEX19 binds ABCD3 and is required for peroxisomal membrane targeting
  - statement: PEX19 is predominantly cytoplasmic
- id: PMID:10777694
  title: Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the
    peroxisomal assembly protein PEX19p.
  findings:
  - statement: ABCD3 interacts with PEX19 for peroxisomal targeting
- id: PMID:11248239
  title: Characterization and functional analysis of the nucleotide binding fold in human peroxisomal
    ATP binding cassette transporters.
  findings:
  - statement: PMP70 NBF binds ATP with KM of 8.2 uM
  - statement: ATP-specific, no GTPase activity
  - statement: G478R mutation decreases ATP binding; S572I decreases ATPase activity
  - statement: NBF mutations do not affect dimerization
- id: PMID:11453642
  title: Targeting elements in the amino-terminal part direct the human 70-kDa peroxisomal integral membrane
    protein (PMP70) to peroxisomes.
  findings:
  - statement: N-terminal targeting elements required for peroxisomal localization
- id: PMID:11590176
  title: Two different targeting signals direct human peroxisomal membrane protein 22 to peroxisomes.
  findings: []
- id: PMID:11883941
  title: Two splice variants of human PEX19 exhibit distinct functions in peroxisomal assembly.
  findings: []
- id: PMID:14709540
  title: PEX19 is a predominantly cytosolic chaperone and import receptor for class 1 peroxisomal membrane
    proteins.
  findings:
  - statement: ABCD3 is a class 1 PMP that uses PEX19 as chaperone/import receptor
- id: PMID:16344115
  title: Role of Pex19p in the targeting of PMP70 to peroxisome.
  findings:
  - statement: PEX19 N-terminal region interacts with ABCD3 N-terminus (aa 1-61)
  - statement: Required for peroxisomal targeting
- id: PMID:17542813
  title: 'Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein
    (ALDP/ABCD1) with naturally occurring missense mutations.'
  findings:
  - statement: ABCD3 (PMP70) used as peroxisomal marker; confirmed peroxisomal localization
- id: PMID:17609205
  title: 'Live cell FRET microscopy: homo- and heterodimerization of two human peroxisomal ABC transporters,
    the adrenoleukodystrophy protein (ALDP, ABCD1) and PMP70 (ABCD3).'
  findings:
  - statement: ABCD3 forms homodimers in living cells (FRET microscopy)
  - statement: Also forms ABCD1/ABCD3 heterodimers, but ABCD1 homodimers predominate
  - statement: C-terminal 87 amino acids harbor the key dimerization domain
- id: PMID:17761678
  title: Hydrophobic regions adjacent to transmembrane domains 1 and 5 are important for the targeting
    of the 70-kDa peroxisomal membrane protein.
  findings:
  - statement: PMP70 has two distinct peroxisomal targeting signals
  - statement: Hydrophobic regions adjacent to TMD1 and TMD5 are critical
  - statement: L21Q/L22Q/L23Q, I70N/L71Q, I307A/L308A mutations abolish targeting
- id: PMID:19479899
  title: Pex3p-dependent peroxisomal biogenesis initiates in the endoplasmic reticulum of human fibroblasts.
  findings:
  - statement: ABCD3 used as peroxisomal membrane marker
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings:
  - statement: ABCD3 identified in NK cell membrane proteome
- id: PMID:20007743
  title: Multiple organelle-targeting signals in the N-terminal portion of peroxisomal membrane protein
    PMP70.
  findings:
  - statement: N-terminal 80aa segment alone targets to outer mitochondrial membrane
  - statement: TM1 segment alone targets to ER
  - statement: Full N80-TM1-TM2 region targets exclusively to peroxisomes
  - statement: N80 segment suppresses ER-targeting function of TM1
- id: PMID:21102411
  title: Structural basis for docking of peroxisomal membrane protein carrier Pex19p onto its receptor
    Pex3p.
  findings:
  - statement: PEX19/PEX3 docking structure relevant to ABCD3 import pathway
- id: PMID:24333844
  title: A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids.
  findings:
  - statement: Each peroxisomal half-transporter can function as homodimer
  - statement: ABCD3 preferentially transports hydrophilic substrates including long-chain unsaturated,
      branched-chain, and dicarboxylic fatty acids
  - statement: Substrate specificities of ABCD1, ABCD2, and ABCD3 are overlapping but distinct
  - statement: All substrates transported as CoA esters
  - statement: ABCD3 has a specific role in dicarboxylic acid oxidation
- id: PMID:25168382
  title: A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3.
  findings:
  - statement: First ABCD3-deficient patient identified with CBAS5
  - statement: Accumulation of C27-bile acid intermediates in plasma
  - statement: Normal C26:0 beta-oxidation but reduced pristanic acid beta-oxidation
  - statement: Abcd3 KO mice accumulate phytanic acid and C27-bile acid intermediates
  - statement: ABCD3 transports branched-chain fatty acids and C27 bile acids into peroxisomes
  - statement: Critical step in bile acid biosynthesis
- id: PMID:29397936
  title: Characterization of human ATP-binding cassette protein subfamily D reconstituted into proteoliposomes.
  findings:
  - statement: ABCD3 displays stable ATPase activity inhibited by AlF3
  - statement: ABCD3 possesses acyl-CoA thioesterase activity equal to ABCD1/2/4
  - statement: Reconstituted in proteoliposomes for functional characterization
- id: PMID:34564857
  title: The peroxisomal transporter ABCD3 plays a major role in hepatic dicarboxylic fatty acid metabolism
    and lipid homeostasis.
  findings:
  - statement: Abcd3 KO mice show increased hepatic long-chain DCAs (C14-C18)
  - statement: Elevated urinary medium-chain DCAs
  - statement: Hepatomegaly, lipodystrophic phenotype
  - statement: Elevated C27 bile acid precursors DHCA and THCA
  - statement: Deficient ketone body production during fasting
  - statement: Enhanced cholesterol synthesis with decreased de novo lipogenesis
- id: PMID:39223112
  title: Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.
  findings:
  - statement: Cryo-EM structures of ABCD3 bound to phytanoyl-CoA (2.9 A) and ATP (3.2 A)
  - statement: Inward-facing and outward-facing conformational states captured
  - statement: Two phytanoyl-CoA molecules bind individually to each TMD
  - statement: DHCA-CoA and THCA-CoA are ABCD3-specific substrates
  - statement: ATP binding causes scissor-like movement expanding translocation cavity
  - statement: PDB codes 8Z0F and 8Z9X
- id: PMID:40501884
  title: Molecular mechanism of substrate transport by human peroxisomal ABCD3.
  findings:
  - statement: Cryo-EM structures of full-length ABCD3 apo (3.33 A) and phytanoyl-CoA-bound (3.13 A)
  - statement: Both inward-facing conformations as homodimer
  - statement: Substrate binding induces 5-fold increase in ATPase activity
  - statement: Substrate binding reduces NBD separation from 38.18 to 34.28 A
  - statement: Proposed transport cycle with substrate-induced NBD closure
- id: Reactome:R-HSA-382575
  title: ABCD1-3 dimers transfer LCFAs from cytosol to peroxisomal matrix
  findings: []
- id: Reactome:R-HSA-382613
  title: PEX-19 docks ABCD1/D2/D3 to peroximal membrane
  findings: []
- id: Reactome:R-HSA-9603775
  title: PEX3:PEX19:class I PMP dissociates
  findings: []
- id: Reactome:R-HSA-9603784
  title: PEX19:class I PMP binds PEX3
  findings: []
- id: Reactome:R-HSA-9603804
  title: PEX19 binds class I peroxisomal membrane proteins
  findings: []
core_functions:
- molecular_function:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  description: 'ABCD3 is a peroxisomal ABC half-transporter that homodimerizes to form an active ATP-dependent
    transporter. It catalyzes ATP-driven import of fatty acid substrates (as CoA esters) from the cytosol
    into the peroxisomal lumen. Cryo-EM structures reveal an alternating-access mechanism: substrate binding
    to the inward-open state promotes NBD dimerization, ATP binding drives transition to outward-open
    state for substrate release, and ATP hydrolysis resets the transporter [PMID:39223112, PMID:40501884].'
  directly_involved_in:
  - id: GO:0015910
    label: long-chain fatty acid import into peroxisome
  - id: GO:0006635
    label: fatty acid beta-oxidation
  locations:
  - id: GO:0005778
    label: peroxisomal membrane
  supported_by:
  - reference_id: PMID:29397936
    supporting_text: ABCD1-4 displayed stable ATPase activity, which was inhibited by AlF3
  - reference_id: PMID:39223112
    supporting_text: Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal
      matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation
      cavity
  - reference_id: PMID:40501884
    supporting_text: Structural comparison of the apo and substrate bound states demonstrate that the substrate
      interaction brings nucleotide-binding domains closer, providing a mechanistic basis of substrate
      induced ATPase activity
- molecular_function:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  description: ABCD3 has broad substrate specificity among the peroxisomal ABC transporters, preferentially
    importing hydrophilic fatty acid substrates including long-chain unsaturated fatty acids, branched-chain
    fatty acids (pristanic acid), dicarboxylic acids (C14-C18), and bile acid CoA-ester intermediates
    (DHCA-CoA, THCA-CoA). This contrasts with ABCD1 which preferentially transports the most hydrophobic
    VLCFAs [PMID:24333844].
  directly_involved_in:
  - id: GO:0015910
    label: long-chain fatty acid import into peroxisome
  - id: GO:1903512
    label: phytanic acid metabolic process
  locations:
  - id: GO:0005778
    label: peroxisomal membrane
  supported_by:
  - reference_id: PMID:24333844
    supporting_text: most hydrophilic substrates like long-chain unsaturated-, long branched-chain- and
      long-chain dicarboxylic fatty acids by HsABCD3
- molecular_function:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  description: ABCD3 is the peroxisomal transporter responsible for import of C27-bile acid CoA-ester
    intermediates (DHCA-CoA, THCA-CoA) for side-chain shortening to mature C24 bile acids. Loss of ABCD3
    causes CBAS5 with accumulation of bile acid intermediates. Structural studies identify these as ABCD3-specific
    substrates [PMID:25168382, PMID:39223112]. This represents a unique and non-redundant function of
    ABCD3 within the ABCD transporter family.
  directly_involved_in:
  - id: GO:0015721
    label: bile acid and bile salt transport
  - id: GO:0006699
    label: bile acid biosynthetic process
  locations:
  - id: GO:0005778
    label: peroxisomal membrane
  supported_by:
  - reference_id: PMID:25168382
    supporting_text: ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into
      the peroxisome and that this is a crucial step in bile acid biosynthesis
- molecular_function:
    id: GO:0047617
    label: fatty acyl-CoA hydrolase activity
  description: ABCD3 possesses intrinsic thioesterase activity that cleaves fatty acyl-CoAs into free
    fatty acids and CoA. This may be mechanistically coupled to the transport process, with CoA hydrolysis
    occurring during or after substrate translocation [PMID:29397936]. The cryo-EM studies suggest substrates
    may be released either intact or after hydrolysis [PMID:40501884].
  locations:
  - id: GO:0005778
    label: peroxisomal membrane
  supported_by:
  - reference_id: PMID:29397936
    supporting_text: ABCD1-4 were found to possess an equal levels of acyl-CoA thioesterase activity
suggested_questions:
- question: Does ABCD3 transport bile acid CoA-esters as intact molecules or does it hydrolyze the CoA
    moiety during translocation? The cryo-EM structures show substrate bound as intact CoA-ester, but
    thioesterase activity has been demonstrated. What is the physiological transport form?
- question: What is the functional significance of ABCD3 heterodimers with ABCD1 or ABCD2? Do heterodimers
    have different substrate preferences than homodimers?
- question: The Abcd3 KO mice show a lipodystrophic phenotype with altered cholesterol synthesis and decreased
    lipogenesis. Are these direct consequences of impaired peroxisomal import or secondary metabolic adaptations?
suggested_experiments:
- description: In vitro reconstituted transport assays using ABCD3 proteoliposomes with radiolabeled bile
    acid CoA-esters (DHCA-CoA, THCA-CoA) to directly demonstrate ATP-dependent transport of these specific
    substrates and determine whether they are transported intact or hydrolyzed during translocation.
- description: Cryo-EM structures of ABCD3 bound to bile acid CoA-ester substrates to complement the existing
    phytanoyl-CoA-bound structures and reveal any substrate-specific binding modes.
- description: Functional characterization of ABCD3/ABCD1 and ABCD3/ABCD2 heterodimers reconstituted in
    proteoliposomes to determine substrate specificity and transport rates compared to homodimers.