id: P05166
gene_symbol: PCCB
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PCCB encodes the beta (carboxyltransferase) subunit of mitochondrial
  propionyl-CoA carboxylase (PCC; EC 6.4.1.3), a biotin-dependent carboxylase of
  the mitochondrial matrix. The functional holoenzyme is an alpha6-beta6
  dodecamer (~750 kDa) built around a central beta6 hexamer core decorated by six
  PCCA (alpha) subunits. Within PCC, the alpha subunit carboxylates biotin on its
  biotin-carboxyl-carrier (BCCP) domain in an ATP-dependent step, and the beta
  subunit then transfers the carboxyl group from carboxybiotin to propionyl-CoA,
  converting propanoyl-CoA + hydrogencarbonate + ATP to (S)-methylmalonyl-CoA +
  ADP + phosphate. This is the committed step of propionyl-CoA (propionate)
  catabolism: propionyl-CoA arises from degradation of the amino acids
  isoleucine, valine, methionine and threonine, of odd-chain fatty acids, and of
  the cholesterol side chain, and the methylmalonyl-CoA product is isomerized and
  converted to succinyl-CoA, an anaplerotic entry point into the tricarboxylic
  acid cycle. The enzyme is promiscuous, also carboxylating butyryl-CoA and
  acetyl-CoA at much lower rates. Biallelic loss-of-function variants in PCCB
  (or PCCA) cause propionic acidemia, an autosomal recessive organic acidemia
  characterized by metabolic acidosis, ketosis, hyperammonemia, and multi-organ
  complications; many PCCB missense variants act by impairing holoenzyme
  assembly and stability rather than by directly abolishing catalysis.
alternative_products:
- name: '1'
  id: P05166-1
- name: '2'
  id: P05166-2
  sequence_note: VSP_042568
existing_annotations:
- 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 of the PCC beta
      subunit. PCC is a well-established mitochondrial matrix enzyme, so
      mitochondrion is correct but less specific than the matrix annotations.
    action: ACCEPT
    reason: >-
      PCC is a mitochondrial biotin-dependent enzyme; the beta subunit is imported
      into the mitochondrial matrix. Mitochondrion is correct at a broader
      granularity than mitochondrial matrix (GO:0005759), which is the precise
      compartment.
    supported_by:
    - reference_id: PMID:8188292
      supporting_text: >-
        Propionyl-CoA carboxylase (PCC) is a mitochondrial, biotin-dependent
        enzyme, composed of an equal number of alpha and beta subunits
- 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
      defining molecular function of the PCC beta (carboxyltransferase) subunit
      and is directly supported by biochemical characterization of the human
      enzyme.
    action: ACCEPT
    reason: >-
      Core molecular function. The beta subunit supplies the carboxyltransferase
      activity that transfers the carboxyl group from carboxybiotin to
      propionyl-CoA; the holoenzyme carboxylates propionyl-CoA to
      (S)/D-methylmalonyl-CoA. Consistent with the IDA/EXP annotations from the
      purified human enzyme.
    supported_by:
    - reference_id: PMID:20725044
      supporting_text: >-
        the alpha-subunit contains the biotin carboxylase (BC) and biotin carboxyl
        carrier protein (BCCP) domains, whereas the beta-subunit supplies the
        carboxyltransferase (CT) activity
- term:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation of propionyl-CoA carboxylase activity mapped from
      RHEA:23720 / EC 6.4.1.3. Concordant with the experimental molecular
      function and the UniProt catalytic activity statement.
    action: ACCEPT
    reason: >-
      Correct core molecular function; the RHEA/EC mapping matches the
      experimentally characterized reaction (propanoyl-CoA + hydrogencarbonate +
      ATP = (S)-methylmalonyl-CoA + ADP + phosphate).
    supported_by:
    - reference_id: PMID:15890657
      supporting_text: >-
        Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme
        that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation to mitochondrial matrix from the UniProt subcellular
      location vocabulary mapping (SL-0170). Matches the experimental IDA/NAS/TAS
      matrix annotations.
    action: ACCEPT
    reason: >-
      Correct core localization. The mature beta subunit resides in the
      mitochondrial matrix, where the PCC holoenzyme functions.
    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:0009062
    label: fatty acid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to fatty acid catabolic process. Odd-chain fatty
      acid beta-oxidation is one of the sources of the propionyl-CoA substrate, so
      PCC contributes to fatty acid catabolism, but this is a broad framing rather
      than PCC's direct committed reaction (propionate catabolism).
    action: KEEP_AS_NON_CORE
    reason: >-
      Not wrong: propionyl-CoA is the end product of beta-oxidation of odd-numbered
      fatty acids, and PCC clears it. However this is a downstream/broad
      biological-process framing; the precise, direct role is propionate catabolic
      process (proposed as a core BP). Keep as non-core contextual annotation.
    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:0016874
    label: ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation to the generic parent term ligase
      activity, from the CoA carboxyltransferase C-terminal domain signature
      (IPR011763). The specific activity (propionyl-CoA carboxylase) is
      experimentally established.
    action: MODIFY
    reason: >-
      Ligase activity is far too general for a protein whose specific molecular
      function is known. Propionyl-CoA carboxylase is formally an ATP-dependent
      ligase (EC 6.4.1.3), and the precise term GO:0004658 propionyl-CoA carboxylase
      activity is available and experimentally supported. Replace with the specific
      term.
    proposed_replacement_terms:
    - id: GO:0004658
      label: propionyl-CoA carboxylase activity
    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:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20725044
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation with PCCA (P05165), the obligate alpha partner
      subunit, from the PCC holoenzyme crystal-structure study. The interaction is
      biologically real (PCCB and PCCA form the alpha6-beta6 dodecamer) but the
      bare "protein binding" term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, bare protein binding (GO:0005515) conveys no specific
      molecular function. The meaningful biology (PCCB-PCCA holoenzyme assembly) is
      captured by the catalytic-complex annotation (GO:1902494) and the carboxylase
      MF, so this IPI is redundant/over-annotated as an MF. Not removed, per policy
      on IPI protein-binding annotations.
    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: >-
      IPI protein-binding annotation from the HuRI binary interactome (yeast
      two-hybrid) with ACTN3 (Q08043), a cytoskeletal alpha-actinin. There is no
      biological corroboration for a physical role of the mitochondrial matrix
      enzyme PCCB with a sarcomeric protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding (GO:0005515) is uninformative, and this high-throughput
      binary interactome hit (with a cytoskeletal protein not co-localized with the
      matrix enzyme) is most consistent with a screen artifact. Marked as
      over-annotated rather than removed, per policy on IPI protein-binding
      annotations.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from the BioPlex (AP-MS) interactome with
      PCCA (P05165), the obligate alpha partner subunit. Recapitulates the known
      PCCB-PCCA physical association but via the uninformative "protein binding"
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding (GO:0005515) is uninformative. The captured
      PCCB-PCCA association is already represented by the holoenzyme/complex
      (GO:1902494) and MF annotations. Marked as over-annotated rather than removed,
      per policy on IPI protein-binding annotations.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        PCCB requires PCCA for stability
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      IPI protein-binding annotation from a multimodal cell-map / AP-MS study with
      PCCA (P05165), the obligate alpha partner subunit. Again reflects the known
      PCCB-PCCA association through the uninformative "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding (GO:0005515) is uninformative and redundant with the
      complex and MF annotations that already capture PCCB-PCCA holoenzyme assembly.
      Marked as over-annotated rather than removed, per policy on IPI
      protein-binding annotations.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        PCC is 750 kDa heterododecamer composed of 6 propionyl-CoA carboxylase,
        alpha (PCCA, OMIM 232000) and 6 propionyl-CoA carboxylase, beta subunits
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: NAS
  original_reference_id: PMID:29033250
  qualifier: located_in
  review:
    summary: >-
      ComplexPortal NAS annotation to mitochondrial matrix, consistent with the
      established localization of the PCC holoenzyme.
    action: ACCEPT
    reason: >-
      Correct core localization. Multiple independent lines (IDA, IEA, TAS) place
      PCC 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:0006631
    label: fatty acid metabolic process
  evidence_type: NAS
  original_reference_id: PMID:29033250
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal NAS annotation to the broad term fatty acid metabolic process.
      PCC participates in odd-chain fatty acid catabolism (a source of its
      propionyl-CoA substrate), but this is a high-level parent term, not the
      committed reaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad and contextual. Odd-chain fatty acid metabolism generates the
      propionyl-CoA that PCC carboxylates, so involvement in fatty acid metabolism
      is defensible, but the direct role is propionate catabolic process. Retain as
      non-core.
    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:0009081
    label: branched-chain amino acid metabolic process
  evidence_type: NAS
  original_reference_id: PMID:29033250
  qualifier: involved_in
  review:
    summary: >-
      ComplexPortal NAS annotation reflecting that degradation of the branched-chain
      amino acids isoleucine and valine (and of methionine and threonine) feeds
      propionyl-CoA into the PCC reaction. This is an upstream metabolic-context
      role rather than PCC's direct catalytic step.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct in that Ile/Val (BCAA) catabolism produces propionyl-CoA, the PCC
      substrate; PCC clears this intermediate. But PCC's own reaction is propionate
      catabolism, not BCAA metabolism per se, so retain as a non-core contextual
      annotation.
    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 annotation (CPX-6169, mitochondrial propionyl-CoA carboxylase
      complex) that PCCB is part of a catalytic complex. PCCB is a constitutive
      subunit of the alpha6-beta6 PCC holoenzyme.
    action: ACCEPT
    reason: >-
      Correct and informative: PCCB is an obligate subunit of the PCC catalytic
      holoenzyme (the mitochondrial propionyl-CoA carboxylase complex). Captures the
      PCCB-PCCA assembly better than a bare protein-binding 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:0004658
    label: propionyl-CoA carboxylase activity
  evidence_type: EXP
  original_reference_id: PMID:15890657
  qualifier: enables
  review:
    summary: >-
      Experimental annotation of propionyl-CoA carboxylase activity from
      recombinant human PCC (wild-type and PCCB variants) purified and assayed.
      Directly supports the defining molecular function of the beta subunit.
    action: ACCEPT
    reason: >-
      Core molecular function, experimentally established. The study purified
      recombinant human PCC containing the beta subunit and measured propionyl-CoA
      carboxylase kinetics (kcat/Km), confirming the carboxylase activity.
    supported_by:
    - reference_id: PMID:15890657
      supporting_text: >-
        Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme
        that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics annotation placing PCCB in the mitochondrion,
      from a quantitative high-confidence human mitochondrial proteome study.
      Concordant with the established matrix localization.
    action: ACCEPT
    reason: >-
      Correct localization at the organelle level (less specific than mitochondrial
      matrix). Consistent with all other localization evidence.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        Quantitative high-confidence human mitochondrial proteome and its dynamics
        in cellular context
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:16023992
  qualifier: located_in
  review:
    summary: >-
      IDA annotation to mitochondrial matrix based on direct determination of the
      PCC N-terminal targeting presequence and mature peptide, showing matrix import
      by the classical presequence pathway.
    action: ACCEPT
    reason: >-
      Core localization, directly supported. The study identified the cleavage sites
      and mature amino-termini and demonstrated matrix import of PCC (studied
      alongside its paralog MCC) via cleavable presequences.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: >-
        are imported into the mitochondrial matrix by the classical pathway
        involving cleavable amino-terminal targeting presequences
- 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-inferred (IC, from GO:0004658) annotation to short-chain fatty acid
      catabolic process. Propionyl-CoA (a short-chain acyl-CoA) is catabolized via
      the PCC reaction, so this is defensible, but the precise process term is
      propionate catabolic process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reasonable framing (propionyl-CoA/propionate is a short-chain fatty acid
      derivative and PCC initiates its catabolism), but the direct, specific
      biological process is propionate catabolic process (GO:0019543), proposed as
      the core BP. Retain this broader term as non-core rather than removing it.
    supported_by:
    - reference_id: PMID:6765947
      supporting_text: >-
        The enzyme also catalyzes the carboxylation of acetyl-CoA and butyryl-CoA to
        a limited degree, but not that of crotonyl-CoA
- term:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  evidence_type: IDA
  original_reference_id: PMID:6765947
  qualifier: enables
  review:
    summary: >-
      IDA annotation of propionyl-CoA carboxylase activity from the enzyme purified
      to homogeneity from normal human liver, with measured kinetics for
      propionyl-CoA, ATP and bicarbonate. This is the strongest experimental support
      for the core molecular function.
    action: ACCEPT
    reason: >-
      Core molecular function, directly demonstrated on the human enzyme. The
      purified PCC (alpha/beta) carboxylates propionyl-CoA with defined Km values.
    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: TAS
  original_reference_id: Reactome:R-HSA-3065959
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to mitochondrial matrix (in the context of PCC
      degradation). Consistent with the established matrix localization of PCCB.
    action: ACCEPT
    reason: >-
      Correct core localization, concordant with 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:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3323111
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to mitochondrial matrix (from the "Cytosolic
      carboxylases translocate to mitochondrial matrix" reaction). Represents the
      functional matrix compartment of PCC.
    action: ACCEPT
    reason: >-
      Correct core localization. This reaction models the endpoint of import into
      the matrix, where PCC functions.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: >-
        are imported into the mitochondrial matrix by the classical pathway
        involving cleavable amino-terminal targeting presequences
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71031
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to mitochondrial matrix from the PCC catalytic
      reaction (propionyl-CoA + CO2 + ATP <=> D-methylmalonyl-CoA + ADP +
      orthophosphate). Places the enzymatic activity in the matrix.
    action: ACCEPT
    reason: >-
      Correct core localization; the PCC-catalyzed reaction occurs in the
      mitochondrial matrix.
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        catalyzes the carboxylation of propionyl-CoA with bicarbonate producing
        methylmalonyl-CoA which is then converted to succinyl-CoA
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838081
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to mitochondrial matrix (LONP1-mediated matrix protein
      degradation context). Consistent with PCCB being a matrix protein.
    action: ACCEPT
    reason: >-
      Correct core localization, concordant with all other evidence for matrix
      residence.
    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-9838093
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to mitochondrial matrix (LONP1 binds mitochondrial
      matrix proteins context). Consistent with the established matrix localization.
    action: ACCEPT
    reason: >-
      Correct core localization, concordant with 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:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2993447
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to cytosol from the "HLCS biotinylates 6x(PCCA:PCCB)"
      reaction, which Reactome models in the cytosol prior to mitochondrial import.
      This reflects a transient biogenesis stage, not the mature functional
      compartment.
    action: KEEP_AS_NON_CORE
    reason: >-
      The functional PCC holoenzyme acts in the mitochondrial matrix. Reactome
      places biotinylation/assembly steps in the cytosol before import, so this
      cytosol annotation captures a transient itinerary compartment. Retain as
      non-core rather than treating it as a functional localization.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: >-
        are imported into the mitochondrial matrix by the classical pathway
        involving cleavable amino-terminal targeting presequences
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3323111
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to cytosol from the "Cytosolic carboxylases
      translocate to mitochondrial matrix" reaction, representing the pre-import
      cytosolic stage of the carboxylase precursor.
    action: KEEP_AS_NON_CORE
    reason: >-
      Transient localization of the newly synthesized precursor before matrix
      import; not the functional compartment. Retain as non-core.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: >-
        are imported into the mitochondrial matrix by the classical pathway
        involving cleavable amino-terminal targeting presequences
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035990
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation to cytosol from the "Defective HLCS does not
      biotinylate 6x(PCCA:PCCB)" reaction, again a cytosolic biogenesis step
      preceding matrix import.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reflects the pre-import cytosolic assembly/biotinylation stage, not the mature
      functional site. Retain as non-core.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: >-
        are imported into the mitochondrial matrix by the classical pathway
        involving cleavable amino-terminal targeting presequences
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:8188292
  qualifier: located_in
  review:
    summary: >-
      TAS annotation to mitochondrion. The microinjection/complementation study
      confirmed that beta subunits are transported into mitochondria and assemble
      with alpha subunits to form functional PCC.
    action: ACCEPT
    reason: >-
      Correct localization at the organelle level (less specific than matrix).
      Directly supported by the demonstration that beta subunits are imported into
      mitochondria and form functional holoenzyme.
    supported_by:
    - reference_id: PMID:8188292
      supporting_text: >-
        the capacity for beta subunits derived from the microinjected cDNA or RNA to
        be transported into mitochondria and assembled with endogenously derived
        alpha subunits to form functional PCC
- term:
    id: GO:0019543
    label: propionate catabolic process
  evidence_type: IC
  original_reference_id: PMID:29033250
  qualifier: involved_in
  review:
    summary: >-
      Proposed core biological-process annotation. PCC catalyzes the committed step
      of propionyl-CoA (propionate) catabolism, converting propionyl-CoA to
      methylmalonyl-CoA en route to succinyl-CoA; loss of PCC activity in propionic
      acidemia directly reflects a defect in propionate catabolism.
    action: NEW
    reason: >-
      GOA currently annotates PCCB only to broader/adjacent process terms (fatty
      acid catabolic/metabolic process, short-chain fatty acid catabolic process,
      branched-chain amino acid metabolic process). The precise, direct biological
      process is propionate catabolic process, which is the process decreased in
      propionic acidemia (per the disorder knowledge base). Inferred (IC) from the
      established propionyl-CoA carboxylase activity (GO:0004658).
    supported_by:
    - reference_id: PMID:29033250
      supporting_text: >-
        catalyzes the carboxylation of propionyl-CoA with bicarbonate producing
        methylmalonyl-CoA which is then converted to succinyl-CoA, an intermediate
        in the tricarboxylic acid cycle
core_functions:
- description: >-
    Carboxyltransferase subunit of the mitochondrial propionyl-CoA carboxylase
    holoenzyme; transfers the carboxyl group from carboxybiotin to propionyl-CoA,
    carboxylating propionyl-CoA to (S)-methylmalonyl-CoA in the committed step of
    propionate catabolism.
  molecular_function:
    id: GO:0004658
    label: propionyl-CoA carboxylase activity
  directly_involved_in:
  - id: GO:0019543
    label: propionate catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  in_complex:
    id: GO:1902494
    label: catalytic complex
  supported_by:
  - reference_id: PMID:20725044
    supporting_text: >-
      the alpha-subunit contains the biotin carboxylase (BC) and biotin carboxyl
      carrier protein (BCCP) domains, whereas the beta-subunit supplies the
      carboxyltransferase (CT) activity
  - 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: >-
    Are any of the reported minor substrate activities of PCC (butyryl-CoA,
    acetyl-CoA) physiologically relevant in humans, or purely in vitro
    promiscuity?
- question: >-
    Do the proposed non-catalytic/moonlighting roles of the PCCB precursor in the
    cytosol (e.g., reported interactions with glucokinase or the mineralocorticoid
    receptor) have any physiological significance, or are they artifacts?
suggested_experiments:
- description: >-
    Structure-guided kinetic characterization of additional PCCB
    carboxyltransferase active-site residues to distinguish variants that impair
    catalysis from those that impair holoenzyme assembly.
  hypothesis: >-
    Some PCCB pathogenic variants abolish carboxyltransferase catalysis directly,
    whereas others reduce activity indirectly by destabilizing the alpha6-beta6
    holoenzyme.
- description: >-
    Quantitative mitochondrial import and holoenzyme-assembly assays comparing
    PCCB isoform 1 and isoform 2 to determine whether the alternative splice
    product forms functional PCC.
  hypothesis: >-
    PCCB isoform 2 (VSP_042568) differs in its capacity to assemble into a
    catalytically competent holoenzyme.
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: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: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:15890657
  title: Characterization of four variant forms of human propionyl-CoA carboxylase
    expressed in Escherichia coli.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Verified against cached abstract; establishes PCC as a biotin-dependent
      mitochondrial enzyme catalyzing propionyl-CoA to D-methylmalonyl-CoA and
      characterizes PCCB pathogenic variants (assembly defects). Supports the EXP
      propionyl-CoA carboxylase activity annotation.
- id: PMID:16023992
  title: Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA
    carboxylase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Title foregrounds MCC, but the study explicitly also defines the mitochondrial
      targeting presequence and mature N-terminus of propionyl-CoA carboxylase and
      demonstrates matrix import; correct source for the IDA mitochondrial matrix
      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: >-
      Full text available; defines the alpha6-beta6 dodecamer architecture and that
      the beta subunit supplies the carboxyltransferase activity. Supports subunit
      composition, complex membership, and MF.
- id: PMID:29033250
  title: Propionyl-CoA carboxylase - A review.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Comprehensive review; verified full text supports the reaction, substrate
      sources (c-VOMIT), matrix localization, holoenzyme composition, and disease
      links used throughout this review.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Large-scale yeast two-hybrid interactome; the PCCB-ACTN3 hit is not
      biologically corroborated for a mitochondrial matrix enzyme and is most likely
      a high-throughput artifact. Supports only a bare protein-binding IPI.
- 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 AP-MS interactome; the reported PCCB-PCCA interaction is the genuine
      obligate partner association but is captured more informatively by the complex
      and MF annotations than by bare protein binding.
- 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 study supporting mitochondrial
      localization (HTP) of PCCB; concordant with matrix annotations.
- 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 / AP-MS study; the reported PCCB-PCCA interaction is the
      genuine partner-subunit association, redundant with the complex/MF
      annotations. Supports only a bare protein-binding IPI.
- 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: >-
      Purified the human enzyme to homogeneity, established alpha/beta subunit
      composition and biotin content, and measured propionyl-CoA carboxylase
      kinetics. Primary experimental support for the core MF (IDA) and substrate
      properties.
- id: PMID:8188292
  title: Correction of the metabolic defect in propionic acidemia fibroblasts by microinjection
    of a full-length cDNA or RNA transcript encoding the propionyl-CoA carboxylase
    beta subunit.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloned full-length human PCCB, demonstrated mitochondrial import and assembly
      of beta subunits into functional PCC, and corrected the PA fibroblast defect.
      Basis for the RecName evidence and the TAS mitochondrion annotation.
- 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: []
- id: Reactome:R-HSA-9838081
  title: LONP1 degrades mitochondrial matrix proteins
  findings: []
- id: Reactome:R-HSA-9838093
  title: LONP1 binds mitochondrial matrix proteins
  findings: []