id: P16219
gene_symbol: ACADS
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ACADS (short-chain specific acyl-CoA dehydrogenase, SCAD; also butyryl-CoA dehydrogenase;
  EC 1.3.8.1) is a mitochondrial matrix flavoenzyme that catalyzes the first, committed step
  of fatty acid beta-oxidation for short-chain substrates. It performs the FAD-dependent
  alpha,beta-dehydrogenation of saturated short-chain (C4-C6) acyl-CoA thioesters to the
  corresponding trans-2-enoyl-CoA, with the optimum substrate being butyryl-CoA (C4), passing
  the abstracted electrons to electron-transfer flavoprotein (ETF). The mature protein is a
  soluble homotetramer in the mitochondrial matrix, with one non-covalently bound FAD per
  subunit shared at dimer interfaces. SCAD belongs to the acyl-CoA dehydrogenase family and
  is most active in tissues with high beta-oxidation flux such as liver and skeletal muscle.
  Loss-of-function and common susceptibility variants in ACADS cause short-chain acyl-CoA
  dehydrogenase deficiency (ACADSD), a defect of mitochondrial fatty acid oxidation marked by
  ethylmalonic aciduria with variable clinical presentations ranging from infantile acidosis
  and muscle weakness to adult lipid-storage myopathy, and often clinically benign.
existing_annotations:
# --- short-chain fatty acyl-CoA dehydrogenase activity (IBA) ---
- term:
    id: GO:0016937
    label: short-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred short-chain acyl-CoA dehydrogenase activity. This is the precise
      and correct molecular function for ACADS/SCAD, well-supported by direct experimental data
      (purified human SCAD dehydrogenates butyryl-CoA; EC 1.3.8.1 characterization) and by the
      UniProt curated substrate specificity for C4-C6 acyl-CoAs. Appropriate term and specificity.
    action: ACCEPT
    reason: >-
      The IBA propagation gives the most informative MF term and is concordant with the EXP, ISS,
      and IDA evidence. This is the core molecular function of ACADS.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA"
# --- mitochondrion (IBA, is_active_in) ---
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred mitochondrial localization (is_active_in). ACADS is a mitochondrial
      matrix enzyme; this is correct, though less specific than the mitochondrial matrix annotations
      also present.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localization is established by UniProt (matrix), Reactome, HPA immunofluorescence,
      MGI, and the MitoCoP high-confidence mitochondrial proteome. The parent term mitochondrion is
      correct; the more specific matrix term is the preferred core location.
    supported_by:
      - reference_id: PMID:34800366
        supporting_text: "Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context"
# --- fatty acid beta-oxidation using acyl-CoA dehydrogenase (IBA) ---
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement in the acyl-CoA dehydrogenase-mediated step of fatty
      acid beta-oxidation. This accurately captures the biological process in which ACADS acts
      (it catalyzes precisely the acyl-CoA dehydrogenase step) and is more specific than the
      general fatty acid beta-oxidation term.
    action: ACCEPT
    reason: >-
      ACADS performs the first, ACAD-catalyzed step of beta-oxidation for short-chain substrates.
      This is an appropriately specific and correct BP annotation.
    supported_by:
      - reference_id: PMID:8276399
        supporting_text: "one of five homologous dehydrogenases that catalyze the first reaction in the beta-oxidation of fatty acids"
# --- butyrate catabolic process (IBA) ---
- term:
    id: GO:0046359
    label: butyrate catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred butyrate (butanoate) catabolic process. ACADS acts on butyryl-CoA
      (butanoyl-CoA) as its optimum substrate, dehydrogenating it to crotonyl-CoA, i.e. the
      committed catabolic step for the C4 short-chain acyl-CoA. This is a substrate-specific framing
      of the same beta-oxidation step that ACADS catalyzes.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation is reasonable given butyryl-CoA is the optimal substrate, but it is a narrow
      substrate-specific restatement of the core short-chain fatty acid beta-oxidation role rather
      than an independent biological process. Retained as non-core.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA"
# --- acyl-CoA dehydrogenase activity (IEA, ARBA) ---
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (ARBA/InterPro) to the parent acyl-CoA dehydrogenase activity term.
      Correct but less specific than the short-chain term (GO:0016937); ACADS is the dedicated
      short-chain family member.
    action: KEEP_AS_NON_CORE
    reason: >-
      The broad parent term is accurate but subsumed by the more specific short-chain ACAD activity
      annotation, which better reflects ACADS substrate specificity.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "Short chain acyl-CoA (SCA), medium chain acyl-CoA (MCA), and isovaleryl-CoA (IV)"
# --- mitochondrion (IEA, ARBA) ---
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      Electronic (ARBA) annotation to mitochondrion. Correct; ACADS is a mitochondrial matrix
      protein. Less specific than the matrix annotations also present.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localization is well established experimentally; this IEA term is consistent
      with all evidence, though the matrix term is preferred for the core location.
    supported_by:
      - reference_id: PMID:34800366
        supporting_text: "Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context"
# --- mitochondrial matrix (IEA, SubCell) ---
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation from UniProt Subcellular Location mapping. ACADS is a soluble
      mitochondrial matrix enzyme; this is the correct, specific compartment.
    action: ACCEPT
    reason: >-
      UniProt records the subcellular location as mitochondrion matrix (ECO:0000250|UniProtKB:Q3ZBF6),
      consistent with ACADS being a soluble matrix beta-oxidation enzyme. This is the preferred
      core localization.
# --- oxidoreductase activity, acting on the CH-CH group of donors (IEA, InterPro) ---
- 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: >-
      InterPro-derived electronic annotation to an intermediate oxidoreductase term. The
      acyl-CoA dehydrogenase reaction is an oxidation of the alpha,beta (C2-C3) CH-CH bond,
      so this parent term is accurate.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct intermediate-level term between general oxidoreductase and the specific short-chain
      ACAD activity; subsumed by the more specific MF annotation.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "Short chain acyl-CoA (SCA), medium chain acyl-CoA (MCA), and isovaleryl-CoA (IV)"
# --- short-chain fatty acyl-CoA dehydrogenase activity (IEA, Rhea/EC) ---
- term:
    id: GO:0016937
    label: short-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation from Rhea/EC (RHEA:24004 butanoyl-CoA, RHEA:43456, RHEA:47196;
      EC 1.3.8.1) mapping to the short-chain ACAD activity term. Correct and concordant with
      the curated catalytic activity in UniProt and the EXP annotation.
    action: ACCEPT
    reason: >-
      Reflects the UniProt-curated EC 1.3.8.1 and Rhea reactions for short-chain acyl-CoA
      dehydrogenation. This is the core molecular function.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA"
# --- fatty acid beta-oxidation using acyl-CoA dehydrogenase (IEA, ARBA) ---
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Electronic (ARBA) annotation duplicating the IBA process annotation. Correct and appropriately
      specific for ACADS, which catalyzes the ACAD step of beta-oxidation.
    action: ACCEPT
    reason: >-
      Consistent with the experimentally and phylogenetically supported role of ACADS in the
      acyl-CoA dehydrogenase step of fatty acid beta-oxidation.
    supported_by:
      - reference_id: PMID:8276399
        supporting_text: "one of five homologous dehydrogenases that catalyze the first reaction in the beta-oxidation of fatty acids"
# --- flavin adenine dinucleotide binding (IEA, InterPro) ---
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-derived FAD binding annotation. ACADS is a flavoprotein binding one FAD per subunit
      (UniProt cofactor; crystal structure 2VIG). FAD is essential for the dehydrogenase reaction.
      Well-supported and correct.
    action: ACCEPT
    reason: >-
      FAD binding is experimentally documented for purified human SCAD (1 mol FAD per subunit) and
      structurally confirmed; this is a genuine and functionally important molecular function.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "each contains 1 mol of FAD per subunit"
# --- medium-chain fatty acyl-CoA dehydrogenase activity (IEA, Rhea) ---
- term:
    id: GO:0070991
    label: medium-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Electronic Rhea-based annotation derived from RHEA:43464 (hexanoyl-CoA, C6). ACADS does
      dehydrogenate hexanoyl-CoA (C6), which UniProt records as a curated catalytic activity
      (ECO:0000269|PubMed:21237683); C6 sits at the boundary between short- and medium-chain.
      However, the defining specificity of ACADS is short-chain (optimum butyryl-CoA, C4), and
      dedicated MCAD (ACADM) handles medium-chain substrates in vivo.
    action: KEEP_AS_NON_CORE
    reason: >-
      The C6 (hexanoyl-CoA) activity is real and machine-derived from a genuine UniProt-curated Rhea
      reaction, so it should not be removed; but it represents the upper boundary of ACADS substrate
      range rather than its core function. Retained as non-core.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "Short chain acyl-CoA (SCA), medium chain acyl-CoA (MCA), and isovaleryl-CoA (IV)"
# --- protein binding (IPI, BioPlex 28514442) ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      IPI annotation from the BioPlex 2.0 high-throughput affinity-purification interactome
      (WITH UniProtKB:P16444, DPEP1). The generic 'protein binding' term is uninformative and
      the reported partner (DPEP1, a membrane dipeptidase) has no established functional
      relationship to short-chain fatty acid oxidation; the interaction is from a proteome-scale
      AP-MS screen rather than a focused study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare 'protein binding' should not be endorsed as it conveys no
      functional information, and this high-throughput interaction is not corroborated by a
      biologically meaningful partnership. Not a core function.
    supported_by:
      - reference_id: PMID:28514442
        supporting_text: "robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks"
# --- protein binding (IPI, BioPlex 33961781) ---
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI annotation from the BioPlex 3.0 high-throughput interactome (WITH UniProtKB:P16444,
      DPEP1). As above, 'protein binding' is uninformative and the partner derives from a
      proteome-scale AP-MS dataset without focused functional follow-up for ACADS.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a high-throughput screen does not inform ACADS function and is
      not a core annotation; retained but flagged as over-annotated.
    supported_by:
      - reference_id: PMID:33961781
        supporting_text: "Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks"
# --- mitochondrion (IDA, HPA) ---
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      IDA annotation from HPA immunofluorescence. ACADS mitochondrial localization is confirmed
      by immunofluorescence and consistent with all other evidence (matrix enzyme).
    action: KEEP_AS_NON_CORE
    reason: >-
      Direct immunofluorescence localization to mitochondria is concordant with the matrix
      localization established by UniProt, Reactome, and the MitoCoP proteome; the more specific
      mitochondrial matrix term is the preferred core location.
    supported_by:
      - reference_id: PMID:34800366
        supporting_text: "Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context"
# --- mitochondrial matrix (ISS) ---
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      ISS annotation transferring matrix localization from the bovine ortholog (UniProtKB:Q3ZBF6).
      ACADS is a soluble matrix beta-oxidation enzyme; this is the correct, specific compartment.
    action: ACCEPT
    reason: >-
      Matrix localization is the documented UniProt subcellular location and is the appropriate
      core compartment for this soluble matrix flavoenzyme.
# --- short-chain fatty acyl-CoA dehydrogenase activity (EXP, 21237683) ---
- term:
    id: GO:0016937
    label: short-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: EXP
  original_reference_id: PMID:21237683
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) annotation. He et al. 2011 characterized the acyl-CoA dehydrogenase family
      including substrate specificity work that underlies the EC 1.3.8.1 assignment and the curated
      short-chain (C4-C6) substrate range for ACADS in UniProt (ECO:0000269|PubMed:21237683). The
      cached abstract foregrounds the paralogs ACAD9/ACAD10/ACAD11, but the full text and UniProt
      curation establish ACADS short-chain activity; this is the precise, correct MF term.
    action: ACCEPT
    reason: >-
      UniProt cites PubMed:21237683 with experimental evidence (ECO:0000269) for ACADS function,
      catalytic activity, and EC 1.3.8.1, and the curator read the full text. This is the core
      molecular function and should not be removed because the abstract emphasizes paralogs.
    supported_by:
      - reference_id: PMID:21237683
        supporting_text: "the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of"
# --- mitochondrion (HTP, 34800366) ---
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      HTP annotation from the MitoCoP high-confidence human mitochondrial proteome (Morgenstern
      et al. 2021). ACADS is identified as a high-confidence mitochondrial protein, consistent
      with all targeted evidence.
    action: KEEP_AS_NON_CORE
    reason: >-
      A rigorous, multi-dimensional mitochondrial proteomics study confirms ACADS mitochondrial
      localization, reinforcing the matrix localization established by other methods; the more
      specific mitochondrial matrix term is the preferred core location.
    supported_by:
      - reference_id: PMID:34800366
        supporting_text: "Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context"
# --- acyl-CoA dehydrogenase activity (ISS) ---
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS annotation transferring acyl-CoA dehydrogenase activity from the bovine ortholog. Correct
      parent term; the short-chain child term (GO:0016937) better reflects ACADS specificity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but broad; subsumed by the specific short-chain ACAD activity annotation.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "Short chain acyl-CoA (SCA), medium chain acyl-CoA (MCA), and isovaleryl-CoA (IV)"
# --- acyl-CoA dehydrogenase activity (IMP, 11134486) ---
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: IMP
  original_reference_id: PMID:11134486
  qualifier: enables
  review:
    summary: >-
      IMP annotation based on functional characterization of ACADS variants. Corydon et al. showed
      that disease and susceptibility variants reduce or abolish SCAD activity, supporting that the
      protein enables acyl-CoA dehydrogenase activity. Correct, though the short-chain term is more
      specific.
    action: KEEP_AS_NON_CORE
    reason: >-
      Variant studies directly demonstrate ACADS acyl-CoA dehydrogenase activity (e.g. variants with
      reduced/abolished activity). The parent term is correct but subsumed by the specific
      short-chain ACAD activity (GO:0016937); retained as non-core for consistency.
    supported_by:
      - reference_id: PMID:11134486
        supporting_text: "functional SCAD deficiency due to the presence of susceptibility SCAD gene variations, i.e. 625G>A and 511C>T"
# --- short-chain fatty acyl-CoA dehydrogenase activity (ISS) ---
- term:
    id: GO:0016937
    label: short-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: >-
      ISS annotation transferring the specific short-chain ACAD activity from the bovine ortholog.
      Concordant with the EXP, IBA and IEA evidence; correct core molecular function.
    action: ACCEPT
    reason: >-
      Specific and accurate MF term, supported by orthology and direct experimental data.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA"
# --- acyl-CoA dehydrogenase activity (IDA, 3597357) ---
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:3597357
  qualifier: enables
  review:
    summary: >-
      IDA annotation from Finocchiaro et al. 1987, who purified human liver short-chain acyl-CoA
      dehydrogenase to homogeneity and demonstrated dehydrogenation of butyryl-CoA to crotonyl-CoA,
      a homotetrameric structure, and 1 mol FAD per subunit with ETF as electron acceptor. This is
      direct biochemical evidence for ACADS enzymatic activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      The foundational purification/enzymology study directly establishes ACADS acyl-CoA
      dehydrogenase activity. The parent term is correct but is subsumed by the more specific
      short-chain ACAD activity (GO:0016937), so it is retained as non-core for consistency.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA"
      - reference_id: PMID:3597357
        supporting_text: "indicating a homotetrameric structure"
# --- fatty acid beta-oxidation using acyl-CoA dehydrogenase (IDA, 3597357) ---
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IDA
  original_reference_id: PMID:3597357
  qualifier: involved_in
  review:
    summary: >-
      IDA annotation from Finocchiaro et al. 1987. Purified human SCAD catalyzes the acyl-CoA
      dehydrogenase step of beta-oxidation (butyryl-CoA to crotonyl-CoA), directly supporting
      involvement in this process.
    action: ACCEPT
    reason: >-
      Direct demonstration that ACADS catalyzes the ACAD step of fatty acid beta-oxidation. This is
      the core biological process for ACADS.
    supported_by:
      - reference_id: PMID:3597357
        supporting_text: "The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA"
# --- nucleus (HDA, 21630459) ---
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: >-
      HDA annotation from a human sperm-nucleus proteomics dataset (de Mateo et al. 2011). ACADS is
      a soluble mitochondrial matrix flavoenzyme with a cleaved mitochondrial transit peptide and no
      known nuclear role; its detection in a large sperm-nucleus proteome is best explained by
      mitochondrial/cytoplasmic carryover rather than genuine nuclear localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The nuclear localization is unsupported by ACADS biology (matrix beta-oxidation enzyme) and
      derives from a high-throughput proteomics dataset prone to contamination. It does not reflect
      a real subcellular function and is flagged as over-annotated rather than core.
    supported_by:
      - reference_id: PMID:21630459
        supporting_text: "403 different proteins have been identified from the isolated sperm nuclei"
# --- mitochondrial matrix (TAS, Reactome 77319) ---
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-77319
  qualifier: located_in
  review:
    summary: >-
      TAS annotation from the Reactome reaction "Butanoyl-CoA+FAD => Crotonoyl-CoA+FADH2", placing
      ACADS in the mitochondrial matrix where it catalyzes butyryl-CoA dehydrogenation. Correct
      compartment for this matrix enzyme.
    action: ACCEPT
    reason: >-
      Reactome correctly localizes the ACADS-catalyzed short-chain beta-oxidation step to the
      mitochondrial matrix, concordant with UniProt and proteomics evidence.
# --- mitochondrial matrix (TAS, Reactome 77327) ---
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-77327
  qualifier: located_in
  review:
    summary: >-
      TAS annotation from the Reactome reaction "Hexanoyl-CoA+FAD => trans-Hex-2-enoyl-CoA+FADH2",
      placing ACADS in the mitochondrial matrix for the C6 dehydrogenation step. Correct compartment.
    action: ACCEPT
    reason: >-
      Concordant with the documented matrix localization of this soluble beta-oxidation enzyme.
# --- mitochondrion (IDA, MGI 16729965) ---
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:16729965
  qualifier: located_in
  review:
    summary: >-
      IDA annotation curated by MGI and associated with PMID:16729965 (a study primarily about
      OCTN1/SLC22A4 localization to mitochondria). The cached record is abstract-only and concerns
      a different gene, but mitochondrial localization for ACADS is unambiguous from multiple
      independent lines of evidence, so the localization assigned here is correct.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localization of ACADS is firmly established (UniProt matrix, Reactome, HPA,
      MitoCoP). Per guidance, an experimental localization annotation whose full text we cannot
      read should not be overruled, and the assigned compartment is independently confirmed; the
      more specific mitochondrial matrix term is the preferred core location.
    supported_by:
      - reference_id: PMID:34800366
        supporting_text: "Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context"
# --- acyl-CoA dehydrogenase activity (TAS, 2565344) ---
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: TAS
  original_reference_id: PMID:2565344
  qualifier: enables
  review:
    summary: >-
      TAS annotation from the human SCAD cDNA cloning paper (Naito et al. 1989), which identified
      the gene as encoding short-chain acyl-CoA dehydrogenase. Correct molecular function at the
      parent level; the specific short-chain term is preferred.
    action: KEEP_AS_NON_CORE
    reason: >-
      The cloning paper establishes the identity of ACADS as an acyl-CoA dehydrogenase. Accurate but
      broad; subsumed by the specific short-chain ACAD activity annotation, so retained as non-core
      for consistency.
    supported_by:
      - reference_id: PMID:2565344
        supporting_text: "Complementary DNAs encoding the precursor of human placental short chain"
# --- fatty acid beta-oxidation (TAS, 8276399) ---
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: TAS
  original_reference_id: PMID:8276399
  qualifier: involved_in
  review:
    summary: >-
      TAS annotation from the mouse SCAD cDNA paper (Kelly et al. 1993), which states SCAD is one
      of the homologous dehydrogenases catalyzing the first reaction of fatty acid beta-oxidation
      and acts on short-chain (C4-C6) acyl-CoA. Correct biological process for ACADS.
    action: ACCEPT
    reason: >-
      The (ortholog) cloning paper accurately describes SCAD's role in the first step of fatty acid
      beta-oxidation, a core biological process for ACADS.
    supported_by:
      - reference_id: PMID:8276399
        supporting_text: "one of five homologous dehydrogenases that catalyze the first reaction in the beta-oxidation of fatty acids"
# --- fatty acid beta-oxidation (IC, 11134486) ---
- term:
    id: GO:0006635
    label: fatty acid beta-oxidation
  evidence_type: IC
  original_reference_id: PMID:11134486
  qualifier: involved_in
  review:
    summary: >-
      IC (inferred by curator) annotation deriving the fatty acid beta-oxidation process from the
      ACADS acyl-CoA dehydrogenase molecular function (WITH GO:0003995), based on Corydon et al.
      2001. SCAD deficiency is an inborn error of mitochondrial fatty acid oxidation, consistent
      with this process annotation.
    action: ACCEPT
    reason: >-
      Curator inference from the demonstrated MF to the beta-oxidation process is well-justified;
      ACADS is integral to short-chain fatty acid beta-oxidation, and its deficiency is a FAO
      disorder. This is a core biological process.
    supported_by:
      - reference_id: PMID:11134486
        supporting_text: "Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is considered a rare inherited mitochondrial fatty acid oxidation disorder"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF: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:11134486
  title: Role of common gene variations in the molecular pathogenesis of short-chain
    acyl-CoA dehydrogenase deficiency.
  findings:
    - statement: >-
        SCAD deficiency is an inherited mitochondrial fatty acid oxidation disorder; common
        susceptibility variants 625G>A and 511C>T cause functional SCAD deficiency and predispose
        to ethylmalonic aciduria.
      supporting_text: >-
        functional SCAD deficiency due to the presence of susceptibility SCAD gene variations, i.e.
        625G>A and 511C>T
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Underlies the IMP MF (GO:0003995), IC BP (GO:0006635), and UniProt FUNCTION
      and disease annotations for ACADS. Abstract-only in cache.
- id: PMID:16729965
  title: Novel localization of OCTN1, an organic cation/carnitine transporter, to
    mammalian mitochondria.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Abstract is about OCTN1/SLC22A4 mitochondrial localization, not ACADS. MGI used this work to
      assign an IDA mitochondrion annotation to ACADS (likely as a mitochondrial marker in the
      study); full text unavailable here. The localization itself is independently correct, so the
      annotation was accepted rather than challenged.
- id: PMID:21237683
  title: Identification and characterization of new long chain acyl-CoA dehydrogenases.
  findings:
    - statement: >-
        Acyl-CoA dehydrogenases participate in consecutive cycles of beta-oxidation to generate
        acetyl-CoA and reducing equivalents; the paper characterizes ACAD family members and
        underlies the curated short-chain substrate specificity for ACADS.
      supporting_text: >-
        the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt cites this with experimental evidence (ECO:0000269) for ACADS FUNCTION, catalytic
      activity, and EC 1.3.8.1. Abstract foregrounds ACAD9/10/11 paralogs, but the full text and
      UniProt curation support ACADS short-chain activity; the EXP annotation was retained.
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large sperm-nucleus proteomics dataset that is the basis for a spurious nucleus annotation
      on ACADS (a mitochondrial matrix enzyme). Most consistent with contamination/carryover;
      annotation marked over-annotated.
- id: PMID:2565344
  title: Molecular cloning and nucleotide sequence of complementary DNAs encoding
    human short chain acyl-coenzyme A dehydrogenase and the study of the molecular
    basis of human short chain acyl-coenzyme A dehydrogenase deficiency.
  findings:
    - statement: >-
        Cloned and sequenced cDNA encoding the 412-aa precursor of human short-chain acyl-CoA
        dehydrogenase (SCAD), with a 24-aa leader and 388-aa mature protein, related to MCAD.
      supporting_text: >-
        Complementary DNAs encoding the precursor of human placental short chain
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Foundational cloning paper establishing the identity of ACADS; basis for TAS MF annotation.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
    - statement: >-
        ACADS is a member of the high-confidence human mitochondrial proteome (MitoCoP).
      supporting_text: >-
        Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular
        context
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Rigorous mitochondrial proteomics supporting ACADS mitochondrial localization (HTP).
- id: PMID:3597357
  title: Purification and properties of short chain acyl-CoA, medium chain acyl-CoA,
    and isovaleryl-CoA dehydrogenases from human liver.
  findings:
    - statement: >-
        Human liver SCAD was purified to homogeneity; it is a homotetramer with 1 mol FAD per
        subunit, uses ETF as electron acceptor, and converts butyryl-CoA to crotonyl-CoA.
      supporting_text: >-
        The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV
        dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive biochemical characterization of human SCAD; basis for IDA MF/BP annotations and
      core enzymology (homotetramer, FAD, ETF, butyryl-CoA -> crotonyl-CoA).
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 2.0 high-throughput AP-MS interactome; basis for an uninformative 'protein binding'
      annotation (WITH DPEP1). Marked over-annotated.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 high-throughput AP-MS interactome; basis for an uninformative 'protein binding'
      annotation (WITH DPEP1). Marked over-annotated.
- id: PMID:8276399
  title: Cloning and characterization of the mouse short-chain acyl-CoA dehydrogenase
    cDNA.
  findings:
    - statement: >-
        SCAD is one of the homologous dehydrogenases catalyzing the first reaction of fatty acid
        beta-oxidation, with short-chain (C4-C6) acyl-CoA substrates.
      supporting_text: >-
        one of five homologous dehydrogenases that catalyze the first reaction in the beta-oxidation
        of fatty acids
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Mouse ortholog cloning paper; clearly states the SCAD role in the first step of beta-oxidation
      and short-chain substrate specificity. Basis for TAS BP annotation.
- id: Reactome:R-HSA-77319
  title: Butanoyl-CoA+FAD => Crotonoyl-CoA+FADH2
  findings: []
- id: Reactome:R-HSA-77327
  title: Hexanoyl-CoA+FAD => trans-Hex-2-enoyl-CoA+FADH2
  findings: []
core_functions:
- description: >-
    ACADS catalyzes the first, FAD-dependent step of mitochondrial fatty acid beta-oxidation for
    short-chain substrates: the alpha,beta-dehydrogenation of saturated short-chain (C4-C6)
    acyl-CoA thioesters to the corresponding trans-2-enoyl-CoA (optimum substrate butyryl-CoA),
    transferring electrons to electron-transfer flavoprotein (ETF). It acts as a soluble
    homotetramer in the mitochondrial matrix with one FAD per subunit.
  molecular_function:
    id: GO:0016937
    label: short-chain fatty acyl-CoA dehydrogenase activity
  directly_involved_in:
  - id: GO:0006635
    label: fatty acid beta-oxidation
  - id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:3597357
    supporting_text: "The products of SCA dehydrogenase/butyryl-CoA, MCA dehydrogenase/octanoyl-CoA, and IV dehydrogenase/isovaleryl-CoA reactions were identified as crotonyl-CoA"
  - reference_id: PMID:3597357
    supporting_text: "each contains 1 mol of FAD per subunit"
  - reference_id: PMID:8276399
    supporting_text: "one of five homologous dehydrogenases that catalyze the first reaction in the beta-oxidation of fatty acids"
- description: >-
    Cofactor binding required for catalysis. Each SCAD subunit binds one non-covalently associated
    FAD, the redox cofactor that accepts the two electrons removed from the short-chain acyl-CoA
    substrate before passing them to electron-transfer flavoprotein (ETF); FAD is essential for
    dehydrogenase activity.
  molecular_function:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  directly_involved_in:
  - id: GO:0006635
    label: fatty acid beta-oxidation
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:3597357
    supporting_text: "each contains 1 mol of FAD per subunit"
proposed_new_terms: []
suggested_questions:
- question: >-
    What accounts for the wide variability in clinical severity of ACADS deficiency, given that
    common susceptibility variants (625G>A, 511C>T) are frequent in the general population and many
    individuals with ethylmalonic aciduria are asymptomatic?
- question: >-
    Beyond energy-yielding short-chain fatty acid beta-oxidation, does ACADS contribute to the
    catabolism of specific short-chain acyl-CoA pools (e.g. butyryl-CoA derived from amino acid or
    microbial-derived butyrate metabolism) in particular tissues?
suggested_experiments:
- description: >-
    Quantitative measurement of short-chain acyl-CoA flux (C4-C6) in tissues or cell models with
    defined ACADS genotypes (including the common 625G>A and 511C>T variants) to define the
    genotype-to-biochemical-phenotype relationship and the functional threshold for ethylmalonic
    aciduria.
- description: >-
    Structure-guided enzyme kinetics across the C4-C8 acyl-CoA range using purified recombinant
    human SCAD to precisely delimit the short-chain specificity boundary (especially the extent of
    C6/hexanoyl-CoA activity) relative to MCAD, clarifying the medium-chain annotation.