id: P05165
gene_symbol: PCCA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PCCA encodes the biotin-containing alpha subunit of mitochondrial propionyl-CoA
  carboxylase (PCC; EC 6.4.1.3), a biotin-dependent carboxylase of the mitochondrial
  matrix. PCC catalyses the first, committed, ATP-dependent step of propionyl-CoA
  catabolism, converting propanoyl-CoA + bicarbonate + ATP into (S)-methylmalonyl-CoA
  + ADP + phosphate; the methylmalonyl-CoA product is subsequently converted to
  succinyl-CoA and enters the tricarboxylic acid cycle. Propionyl-CoA arises from the
  catabolism of the amino acids isoleucine, valine, methionine and threonine, of
  odd-chain fatty acids, and of cholesterol. The functional holoenzyme is a large
  alpha6-beta6 dodecamer (~750 kDa) built from six PCCA (alpha) and six PCCB (beta)
  subunits. The alpha subunit carries the biotin carboxylase (BC) domain and the
  C-terminal biotin-carboxyl-carrier-protein (BCCP) domain to which biotin is
  covalently attached (at Lys694, by holocarboxylase synthetase); it binds ATP and
  bicarbonate and catalyses the Mg2+-dependent carboxylation of biotin, whereas the
  beta subunit (PCCB) supplies the carboxyltransferase activity that transfers the
  carboxyl group to propionyl-CoA. The alpha subunit is synthesized with a cleavable
  N-terminal mitochondrial targeting presequence and matures in the matrix. Loss of
  PCC activity through biallelic pathogenic variants in PCCA (or PCCB) causes propionic
  acidemia, an autosomal recessive organic acidemia.
alternative_products:
- name: '1'
  id: P05165-1
- name: '2'
  id: P05165-2
  sequence_note: VSP_039857
- name: '3'
  id: P05165-3
  sequence_note: VSP_044458
existing_annotations:
- term:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred propionyl-CoA carboxylase activity. This is the core,
      defining molecular function of PCCA as the biotin-containing alpha subunit of the
      PCC holoenzyme, directly supported by biochemistry and disease genetics.
    action: ACCEPT
    reason: >-
      Well-supported core function; the IBA is at the correct level of specificity and
      concordant with experimental (IDA/IMP) annotations and the EC 6.4.1.3 assignment.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation
        of propionyl-CoA to methylmalonyl-CoA and is encoded by the genes PCCA and PCCB
        to form a hetero-dodecamer.
- 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/activity. Correct: PCC is a
      mitochondrial matrix enzyme.
    action: ACCEPT
    reason: >-
      Consistent with experimental matrix localization (below); mitochondrion is a
      correct, if less specific, compartment for where the enzyme is active.
    supported_by:
    - reference_id: PMID:20725044
      supporting_text: >-
        Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme,
        is essential for the catabolism of the amino acids Thr, Val, Ile and Met,
        cholesterol and fatty acids with an odd number of carbon atoms.
- term:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (RHEA:23720 / EC 6.4.1.3 mapping) assignment of propionyl-CoA
      carboxylase activity. Redundant with, and confirmed by, the experimental IDA/IMP
      annotations of the same term.
    action: ACCEPT
    reason: >-
      Correct core molecular function; the EC/RHEA mapping matches the demonstrated
      catalytic activity.
    supported_by:
    - reference_id: PMID:6765947
      supporting_text: >-
        We have purified propionyl-CoA carboxylase from normal, postmortem human liver
        to homogeneity.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based ATP binding. The alpha subunit contains an ATP-grasp domain and
      catalyses the ATP-dependent carboxylation of biotin; ATP is a substrate of the BC
      reaction (Km ~0.08 mM).
    action: ACCEPT
    reason: >-
      Supported by the catalytic mechanism, the ATP-grasp domain, and multiple ATP
      binding-site features in UniProt; ATP binding is integral to the alpha-subunit
      biotin carboxylase step.
    supported_by:
    - reference_id: PMID:6765947
      supporting_text: >-
        The apparent Km values for ATP, propionyl-CoA, and bicarbonate
        are 0.08 mM, 0.29 mM, and 3.0 mM, respectively.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniProt subcellular location / ARBA) assignment of mitochondrial
      matrix. Correct and concordant with experimental EXP/IDA matrix annotations.
    action: ACCEPT
    reason: >-
      PCC is a matrix enzyme; the electronic assignment matches the curated UniProt
      subcellular location and experimental evidence.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        It is often described as a matrix enzyme because it can dissociate with sonication.
- term:
    id: GO:0009374
    label: biotin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic assignment of biotin binding. Biotin is the obligate cofactor of
      PCC and is covalently attached to the C-terminal biotinyl domain of the alpha
      subunit; each holoenzyme carries biotin almost entirely on the alpha subunit.
    action: ACCEPT
    reason: >-
      Strongly supported: biotin is the defining cofactor of this biotin-dependent
      carboxylase and is carried by PCCA.
    supported_by:
    - reference_id: PMID:6765947
      supporting_text: >-
        Each mole of native enzyme
        contains 4 mol of bound biotin, virtually all of which is found with the larger
        (alpha) subunit.
- term:
    id: GO:0016885
    label: ligase activity, forming carbon-carbon bonds
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: >-
      ARBA electronic assignment of the parent ligase term. This is the correct broad
      catalytic class (EC 6.4 ligases forming C-C bonds) for propionyl-CoA carboxylase,
      but is less informative than the specific GO:0004658 already annotated.
    action: ACCEPT
    reason: >-
      Correct parent activity; not wrong, but subsumed by the more specific
      propionyl-CoA carboxylase activity. Retained as a valid, if general, IEA.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation
        of propionyl-CoA to methylmalonyl-CoA
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based metal ion binding. The alpha-subunit biotin carboxylase/ATP-grasp
      domain binds two divalent metal ions (Mg2+ or Mn2+) per subunit that are required
      for the ATP-dependent carboxylation step.
    action: ACCEPT
    reason: >-
      Supported by UniProt cofactor annotation (binds 2 Mg2+/Mn2+ per subunit) and
      metal-binding site features; a general but correct molecular function.
    supported_by:
    - reference_id: PMID:20725044
      supporting_text: >-
        The active site of the BC domain is conserved with that of E. coli BC, and all
        the residues that interact with the substrates of this reaction have essentially
        the same conformation in both structures
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20725044
  qualifier: enables
  review:
    summary: >-
      IntAct-curated binary interaction with PCCB (P05166), the beta subunit. This is
      the genuine, obligate holoenzyme partnership (alpha6-beta6), but the bare
      "protein binding" term is uninformative about the actual molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation policy, bare protein binding IPIs are not removed. The interaction
      itself (with PCCB) is real and biologically central, but "protein binding" adds no
      functional specificity beyond what is captured by the propionyl-CoA carboxylase
      complex membership; a more informative term (structural constituent of the PCC
      holoenzyme) would be preferable.
    supported_by:
    - reference_id: PMID:20725044
      supporting_text: >-
        The holoenzyme of PCC
        is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      IntAct/HuRI systematic binary interactome hit, here with MCC (MCCC1, P23508), a
      paralogous biotin-dependent carboxylase. Bare "protein binding" from a
      high-throughput all-by-all screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative term from a proteome-scale Y2H screen; not the core function.
      Retained per policy (not removed) but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        Here we present a human 'all-by-all'
        reference interactome map of human binary protein interactions, or 'HuRI'.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IntAct-curated interaction with PCCB (P05166) from a proteome-scale interactome
      study (BioPlex-type). Again the genuine beta-subunit partner, reported via the
      uninformative "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real interaction (PCCB, the holoenzyme partner) but bare protein binding is not
      the core molecular function; retained per policy and flagged as over-annotation.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      IntAct-curated interaction with PCCB (P05166) from a multimodal cell-map / genomics
      study. The beta-subunit partner again, via bare "protein binding".
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Genuine PCCB partnership but uninformative term; retained per policy and flagged
      as over-annotation rather than removed.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional genomics.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (Human Protein Atlas) localization to mitochondrion. Correct,
      if less specific than the matrix annotations.
    action: ACCEPT
    reason: >-
      Direct localization evidence consistent with PCC being a mitochondrial matrix
      enzyme.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        It is often described as a matrix enzyme because it can dissociate with sonication.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: NAS
  original_reference_id: PMID:29033250
  qualifier: located_in
  review:
    summary: >-
      ComplexPortal (CPX-6169) NAS assignment of mitochondrial matrix, from the PCC
      review. Correct compartment for the holoenzyme.
    action: ACCEPT
    reason: >-
      Concordant with experimental EXP/IDA matrix evidence and the curated UniProt
      subcellular location.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        It is often described as a matrix enzyme because it can dissociate with sonication.
- term:
    id: GO:0006631
    label: fatty acid metabolic process
  evidence_type: NAS
  original_reference_id: PMID:29033250
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal NAS: PCC participates in fatty acid metabolism, since propionyl-CoA
      is the end product of beta-oxidation of odd-chain fatty acids and PCC channels it
      into the TCA cycle. Broad process term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real but non-core physiological context. PCC acts on the propionyl-CoA node of
      odd-chain fatty acid catabolism; the direct reaction is more precisely
      propionyl-CoA carboxylation/propionate catabolism than generic fatty acid
      metabolism.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        Disruption of PCC leads to accumulation of odd-chain fatty acids (FA), as
        propionyl-CoA is the end product of beta oxidation of odd-numbered FA.
- term:
    id: GO:0009081
    label: branched-chain amino acid metabolic process
  evidence_type: NAS
  original_reference_id: PMID:29033250
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal NAS: PCC is downstream in the catabolism of branched-chain and other
      amino acids (isoleucine, valine, methionine, threonine) that generate propionyl-CoA.
    action: KEEP_AS_NON_CORE
    reason: >-
      Valid physiological role (Ile and Val catabolism converge on propionyl-CoA), but
      not the direct reaction PCCA catalyses; kept as a relevant non-core process.
      Note GO:0009081 covers isoleucine/leucine/valine; PCC also serves Met/Thr, which
      are not branched-chain, so this term is a partial view of PCC's amino-acid role.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        Propionyl-CoA is produced by catabolism of cholesterol, valine, odd chain fatty
        acids, methionine, isoleucine and threonine
- term:
    id: GO:1902494
    label: catalytic complex
  evidence_type: IPI
  original_reference_id: PMID:20725044
  qualifier: part_of
  review:
    summary: >-
      ComplexPortal IPI: PCCA is part of a catalytic complex, i.e. the alpha6-beta6 PCC
      holoenzyme (ComplexPortal CPX-6169, Mitochondrial propionyl-CoA carboxylase complex).
    action: ACCEPT
    reason: >-
      Correct: PCCA is an obligate structural subunit of the catalytic PCC holoenzyme.
      A dedicated "propionyl-CoA carboxylase complex" GO term does not currently exist
      (only acetyl-CoA and methylcrotonoyl-CoA carboxylase complexes), so the general
      "catalytic complex" is retained rather than modified to a nonexistent term.
    supported_by:
    - reference_id: PMID:20725044
      supporting_text: >-
        The holoenzyme of PCC
        is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: EXP
  original_reference_id: PMID:10101253
  qualifier: located_in
  review:
    summary: >-
      Experimental import/localization: in vitro-expressed PCCA precursor is imported
      into mitochondria and processed to the mature matrix form. Supports mitochondrial
      matrix localization.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for mitochondrial import and maturation, consistent
      with the matrix location of the enzyme.
    supported_by:
    - reference_id: PMID:10101253
      supporting_text: >-
        Both wild-type and mutant proteins were imported into
        mitochondria and processed into the mature form with similar efficiency
- term:
    id: GO:1901290
    label: succinyl-CoA biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8434582
  qualifier: involved_in
  review:
    summary: >-
      IDA (propionate-flux complementation) linking PCCA to production of succinyl-CoA.
      PCC catalyses the first step (propionyl-CoA -> methylmalonyl-CoA); succinyl-CoA is
      the downstream product of the three-step propanoyl-CoA degradation pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      PCC's direct product is (S)-methylmalonyl-CoA, not succinyl-CoA; succinyl-CoA
      formation requires the downstream MCEE and MUT steps. The annotation reflects
      PCCA's contribution to the pathway output rather than its direct catalytic
      product, so it is kept as non-core.
    supported_by:
    - reference_id: PMID:8434582
      supporting_text: >-
        Both
        clones reconstitute propionate flux to normal levels in fibroblasts from
        patients genetically deficient in PCCA (pccA).
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteomics assignment to mitochondrion. Concordant
      with the established mitochondrial matrix localization.
    action: ACCEPT
    reason: >-
      High-confidence mitochondrial proteome evidence consistent with the curated
      compartment; correct though less specific than matrix.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and its dynamics
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:16023992
  qualifier: located_in
  review:
    summary: >-
      Direct evidence: the mature PCCA amino-terminus and cleavable N-terminal targeting
      presequence were defined, showing import into the mitochondrial matrix by the
      classical presequence pathway.
    action: ACCEPT
    reason: >-
      Experimental determination of the mitochondrial targeting signal and mature matrix
      peptide directly supports matrix localization.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: >-
        the two subunits of the enzyme (MCCalpha; MCCbeta)
        are imported into the mitochondrial matrix by the classical pathway involving
        cleavable amino-terminal targeting presequences.
- term:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  evidence_type: IDA
  original_reference_id: PMID:6765947
  qualifier: enables
  review:
    summary: >-
      Direct biochemical demonstration: PCC purified from human liver to homogeneity,
      shown to be a biotin-containing alpha/beta enzyme carboxylating propionyl-CoA with
      defined kinetic parameters. Core molecular function.
    action: ACCEPT
    reason: >-
      Definitive experimental evidence for propionyl-CoA carboxylase activity; anchors
      this as the core function of the enzyme.
    supported_by:
    - reference_id: PMID:6765947
      supporting_text: >-
        The apparent Km values for ATP, propionyl-CoA, and bicarbonate
        are 0.08 mM, 0.29 mM, and 3.0 mM, respectively.
- term:
    id: GO:0019626
    label: short-chain fatty acid catabolic process
  evidence_type: IC
  original_reference_id: PMID:6765947
  qualifier: involved_in
  review:
    summary: >-
      Curator inference (from GO:0004658) that PCC participates in short-chain fatty acid
      catabolism. Propionate/propionyl-CoA is a short-chain acid, but a more precise
      process term is available.
    action: MODIFY
    reason: >-
      The reaction PCC catalyses is specifically the committed step of propionyl-CoA
      catabolism; "short-chain fatty acid catabolic process" is broader and less
      accurate than the dedicated term. Propose replacement with propionyl-CoA catabolic
      process.
    proposed_replacement_terms:
    - id: GO:1902859
      label: propionyl-CoA catabolic process
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        PCC's
        primary function is to catalyze the carboxylation of propionyl-CoA to produce
        methylmalonyl-CoA
- term:
    id: GO:0019626
    label: short-chain fatty acid catabolic process
  evidence_type: IC
  original_reference_id: PMID:8434582
  qualifier: involved_in
  review:
    summary: >-
      Second curator inference (from GO:0004658) of short-chain fatty acid catabolism,
      based on the propionate-flux complementation study. Same over-broad term as above.
    action: MODIFY
    reason: >-
      As above, the direct process is propionyl-CoA / propionate catabolism; replace the
      broad short-chain fatty acid term with the specific propionyl-CoA catabolic process.
    proposed_replacement_terms:
    - id: GO:1902859
      label: propionyl-CoA catabolic process
    supported_by:
    - reference_id: PMID:8434582
      supporting_text: >-
        Both
        clones reconstitute propionate flux to normal levels in fibroblasts from
        patients genetically deficient in PCCA (pccA).
- term:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  evidence_type: IMP
  original_reference_id: PMID:8434582
  qualifier: enables
  review:
    summary: >-
      IMP: recombinant human PCCA rescues (complements) the propionate-flux defect in
      PCCA-deficient (pccA) patient fibroblasts, demonstrating that PCCA is required for
      propionyl-CoA carboxylase activity in cells. Core molecular function.
    action: ACCEPT
    reason: >-
      Genetic complementation directly ties PCCA to the propionyl-CoA carboxylase
      activity and propionate flux; strong support for the core function.
    supported_by:
    - reference_id: PMID:8434582
      supporting_text: >-
        We describe cDNA clones expressing
        human PCCA and complementation of the genetic defect in pccA fibroblasts by
        DNA-mediated gene transfer.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2993447
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS placing PCCA in the cytosol, reflecting the pre-import apo-precursor
      and the Reactome "HLCS biotinylates 6x(PCCA:PCCB)" / cytosolic-to-matrix
      translocation events. PCC is not catalytically active in the cytosol.
    action: KEEP_AS_NON_CORE
    reason: >-
      The functional, biotinylated, active holoenzyme resides in the mitochondrial
      matrix; the cytosolic assignment reflects the transient apo-precursor stage before
      mitochondrial import (any cytosolic biotinylation is likely non-functional). Kept
      as a non-core, transient localization rather than removed.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        The PCCA precursor does not contain biotin until imported into the mitochondrion
        and cleaved
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3323111
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (cytosolic carboxylases translocate to mitochondrial matrix) placing
      the PCCA precursor in the cytosol prior to import.
    action: KEEP_AS_NON_CORE
    reason: >-
      As above: transient pre-import cytosolic localization of the apo-precursor; the
      active enzyme is a matrix enzyme. Non-core.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        The PCCA precursor does not contain biotin until imported into the mitochondrion
        and cleaved
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035990
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS (defective HLCS does not biotinylate 6x(PCCA:PCCB)) placing PCCA in
      the cytosol as part of the biotinylation/multiple-carboxylase-deficiency pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same transient cytosolic apo-precursor context; not the functional compartment.
      Kept as non-core.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        The PCCA precursor does not contain biotin until imported into the mitochondrion
        and cleaved
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3065959
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS assignment of mitochondrial matrix (from the carboxylase degradation
      reaction). Correct functional compartment.
    action: ACCEPT
    reason: >-
      Concordant with experimental matrix evidence; the mature active enzyme is in the
      matrix.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        It is often described as a matrix enzyme because it can dissociate with sonication.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3323111
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS assignment of mitochondrial matrix (post-translocation destination in
      the cytosol->matrix translocation reaction). Correct functional compartment.
    action: ACCEPT
    reason: >-
      Matches the established matrix localization of the mature enzyme.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        It is often described as a matrix enzyme because it can dissociate with sonication.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71031
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS assignment of mitochondrial matrix, associated with the core PCC
      reaction (propionyl-CoA + CO2 + ATP <=> D-methylmalonyl-CoA + ADP + Pi). This is
      the compartment where the catalytic reaction occurs.
    action: ACCEPT
    reason: >-
      Correct: the propionyl-CoA carboxylase reaction takes place in the mitochondrial
      matrix.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        It is often described as a matrix enzyme because it can dissociate with sonication.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:19157941
  qualifier: enables
  review:
    summary: >-
      IPI interaction with holocarboxylase synthetase (HLCS, P50747), the enzyme that
      covalently attaches biotin to PCCA. The study used the PCCA-derived C-terminal p67
      polypeptide (biotinylation site K669/K694) as the HLCS substrate in Y2H and docking
      assays, defining the PCCA-HLCS substrate-enzyme interaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      A real and biologically meaningful interaction (PCCA is the substrate of HLCS-
      mediated biotinylation, essential for activity), but it describes a
      post-translational modification relationship rather than PCCA's own core molecular
      function. "Enzyme binding" is more informative than bare protein binding, so it is
      retained as non-core.
    supported_by:
    - reference_id: PMID:19157941
      supporting_text: >-
        The polypeptide p67 comprises the 67 C-terminal amino acids in human PCC (GenBank
        accession #AAA60035), including the biotin-binding site K669
- term:
    id: GO:0009374
    label: biotin binding
  evidence_type: TAS
  original_reference_id: PMID:3460076
  qualifier: enables
  review:
    summary: >-
      TAS (ProtInc) biotin binding, from the cDNA-cloning paper that identified the
      alpha chain via its conserved Ala-Met-Lys-Met biotin-binding-site motif. Biotin is
      the obligate cofactor carried by PCCA.
    action: ACCEPT
    reason: >-
      Well-established core cofactor relationship; the alpha chain was in fact identified
      through its biotin-binding-site sequence.
    supported_by:
    - reference_id: PMID:3460076
      supporting_text: >-
        One class contained the anticipated Ala-Met-Lys-Met
        sequence, corresponding to the biotin binding site found in several
        biotin-dependent carboxylases, thus confirming the alpha-chain assignment of
        these clones.
core_functions:
- description: >-
    Propionyl-CoA carboxylase alpha subunit: within the alpha6-beta6 PCC holoenzyme, the
    alpha subunit binds ATP and bicarbonate and catalyses the Mg2+-dependent ATP-driven
    carboxylation of its covalently bound biotin, contributing the biotin carboxylase
    half-reaction of propionyl-CoA carboxylase activity (conversion of propanoyl-CoA to
    (S)-methylmalonyl-CoA), the first committed step of propionyl-CoA / propionate
    catabolism in the mitochondrial matrix.
  molecular_function:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  directly_involved_in:
  - id: GO:1902859
    label: propionyl-CoA catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:6765947
    supporting_text: >-
      The apparent Km values for ATP, propionyl-CoA, and bicarbonate
      are 0.08 mM, 0.29 mM, and 3.0 mM, respectively.
  - reference_id: PMID:29033250
    supporting_text: >-
      PCC's
      primary function is to catalyze the carboxylation of propionyl-CoA to produce
      methylmalonyl-CoA
- description: >-
    Biotin cofactor carrier: the alpha subunit carries the C-terminal biotinyl (BCCP)
    domain and binds biotin, which is covalently attached (by holocarboxylase synthetase)
    and is obligately required for catalytic activity of the biotin-dependent carboxylase.
  molecular_function:
    id: GO:0009374
    label: biotin binding
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:6765947
    supporting_text: >-
      Each mole of native enzyme
      contains 4 mol of bound biotin, virtually all of which is found with the larger
      (alpha) subunit.
- description: >-
    ATP binding: the alpha subunit ATP-grasp/biotin carboxylase domain binds ATP (Km
    ~0.08 mM) as a substrate of the ATP-dependent biotin carboxylation step.
  molecular_function:
    id: GO:0005524
    label: ATP binding
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:6765947
    supporting_text: >-
      The apparent Km values for ATP, propionyl-CoA, and bicarbonate
      are 0.08 mM, 0.29 mM, and 3.0 mM, respectively.
proposed_new_terms: []
suggested_questions:
- question: >-
    Do the three PCCA splice isoforms (P05165-1/-2/-3) differ in enzymatic function,
    holoenzyme incorporation, or tissue distribution? Their functional impact has not
    been well characterized.
- question: >-
    Does PCCA (or the PCC holoenzyme) have any moonlighting or regulatory role beyond
    carboxylation, e.g. via its reported acetylation/succinylation and interactions with
    SIRT3/4/5?
suggested_experiments:
- description: >-
    Isoform-resolved enzyme kinetics and holoenzyme-assembly assays for P05165-2 and
    P05165-3 versus the canonical isoform, to determine whether alternative splicing
    alters propionyl-CoA carboxylase activity.
- description: >-
    Quantitative biotinylation/acylation site mapping of PCCA in matched control and
    propionic-acidemia cells to test how post-translational modification state modulates
    PCC activity.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  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:10101253
  title: Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects.
    Identification of five novel mutations, one of them causing instability of the
    protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; provides experimental mitochondrial import/maturation and
      PA-causing PCCA variant data. Supports the EXP mitochondrial-matrix annotation.
- id: PMID:16023992
  title: Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA
    carboxylase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Focuses on MCC but the abstract explicitly reports the mitochondrial targeting
      signal and mature N-terminus of propionyl-CoA carboxylase as a paralog; supports
      the matrix-import IDA for PCCA.
- id: PMID:19157941
  title: N- and C-terminal domains in human holocarboxylase synthetase participate
    in substrate recognition.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Uses the PCCA-derived C-terminal p67 (biotinylation site) as the HLCS substrate;
      documents the PCCA-HLCS enzyme-substrate interaction underlying the enzyme-binding
      annotation.
- id: PMID:20725044
  title: Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme
    A carboxylase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Defines the alpha6-beta6 holoenzyme architecture, BC/BCCP/BT domains of the alpha
      subunit, and BC active site; the source of the PCCB-interaction and catalytic-complex
      annotations.
- id: PMID:29033250
  title: Propionyl-CoA carboxylase - A review.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Authoritative review of PCC structure, function, mechanism, localization, and
      disease; primary basis for the description and process/localization judgments.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI all-by-all binary interactome; source of a systematic PCCA-MCC(MCCC1) hit
      reported as bare protein binding. Not informative about core function.
- 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: >-
      Proteome-scale interactome study; source of a PCCA-PCCB protein-binding hit. The
      interaction (beta subunit) is genuine but the term is uninformative.
- id: PMID:3460076
  title: 'Isolation of cDNA clones coding for the alpha and beta chains of human propionyl-CoA
    carboxylase: chromosomal assignments and DNA polymorphisms associated with PCCA
    and PCCB genes.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identified the PCCA (alpha) cDNA via the conserved biotin-binding-site motif;
      supports the biotin-binding TAS annotation.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-confidence mitochondrial proteome; independent HTP evidence for mitochondrial
      localization of PCCA.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Multimodal cell-map genomics resource; source of a PCCA-PCCB protein-binding hit.
      Genuine partner, uninformative term.
- id: PMID:6765947
  title: Isolation and characterization of propionyl-CoA carboxylase from normal human
    liver. Evidence for a protomeric tetramer of nonidentical subunits.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive biochemical characterization of purified human PCC: biotin content on the
      alpha subunit, kinetic parameters for ATP/propionyl-CoA/bicarbonate, substrate range.
      Primary support for the catalytic-activity, cofactor and ATP-binding core functions.
- id: PMID:8434582
  title: Cloning of functional alpha propionyl CoA carboxylase and correction of enzyme
    deficiency in pccA fibroblasts.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Functional cloning and complementation of PCCA-deficient fibroblasts restoring
      propionate flux; support for the IMP propionyl-CoA carboxylase and pathway annotations.
- id: Reactome:R-HSA-2993447
  title: HLCS biotinylates 6x(PCCA:PCCB)
  findings: []
- id: Reactome:R-HSA-3065959
  title: An unknown protease degrades hCBXs
  findings: []
- id: Reactome:R-HSA-3323111
  title: Cytosolic carboxylases translocate to mitochondrial matrix
  findings: []
- id: Reactome:R-HSA-71031
  title: propionyl-CoA + CO2 + ATP <=> D-methylmalonyl-CoA + ADP + orthophosphate
  findings: []
- id: Reactome:R-HSA-9035990
  title: Defective HLCS does not biotinylate 6x(PCCA:PCCB)
  findings: []