id: Q9HCC0
gene_symbol: MCCC2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: MCCC2 encodes the beta (carboxyltransferase) subunit of mitochondrial
  3-methylcrotonyl-CoA carboxylase (MCC; EC 6.4.1.4), a biotin-dependent carboxylase
  of the leucine catabolic pathway. MCC catalyzes the ATP- and bicarbonate-dependent
  carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. The holoenzyme
  is an alpha6-beta6 dodecamer in which the biotin-containing alpha subunit (MCCC1)
  carries out biotin carboxylation and shuttles the carboxyl group as carboxybiotin,
  while the non-biotin-containing beta subunit encoded by MCCC2 binds the acyl-CoA
  substrate and provides the carboxyltransferase activity that transfers the carboxyl
  group to 3-methylcrotonyl-CoA. The mature protein is imported into the mitochondrial
  matrix via a cleavable N-terminal presequence and belongs to the AccD/PCCB carboxyltransferase
  family, with N- and C-terminal CoA carboxyltransferase domains. Biallelic loss-of-function
  variants in MCCC2 (or in MCCC1) cause 3-methylcrotonyl-CoA carboxylase deficiency
  (3-methylcrotonylglycinuria), an autosomal recessive organic aciduria of leucine
  catabolism with a highly variable phenotype ranging from asymptomatic to severe
  neonatal metabolic decompensation.
alternative_products:
- name: '1'
  id: Q9HCC0-1
- name: '2'
  id: Q9HCC0-2
  sequence_note: VSP_000069
existing_annotations:
- term:
    id: GO:0004485
    label: methylcrotonoyl-CoA carboxylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic (IBA) inference of the core molecular function of MCCC2,
      the carboxyltransferase subunit of 3-methylcrotonyl-CoA carboxylase. The `contributes_to`
      qualifier is appropriate because catalysis is a property of the assembled alpha6-beta6
      holoenzyme; the beta subunit binds the acyl-CoA substrate and provides the carboxyltransferase
      activity but requires the biotin-carrying alpha subunit (MCCC1) for the complete
      reaction.
    action: ACCEPT
    reason: This is the correct, well-supported core molecular function, consistent
      across IBA, experimental (IDA), and EC-based evidence and confirmed by direct
      enzymatic characterization of the recombinant human enzyme.
    supported_by:
    - reference_id: PMID:17360195
      supporting_text: 'protocol has been developed to purify the active MCCC which
        appears to reside in'
    - reference_id: PMID:11170888
      supporting_text: the β subunits contain the binding site for the acyl-CoA substrate
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference that MCCC2 is active in the mitochondrion. This
      is the correct broad localization; the more specific and better-supported location
      is the mitochondrial matrix.
    action: ACCEPT
    reason: Correct compartment. Retained as the general parent of the more specific
      mitochondrial matrix location, which is where MCC actually functions.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference that MCCC2 participates in L-leucine catabolism.
      MCC catalyzes the committed carboxylation step (3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA)
      of the leucine degradation pathway.
    action: ACCEPT
    reason: This is the core biological process for MCCC2, supported experimentally
      (IMP, TAS) and by pathway assignment. Correct and specific.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: 'an enzyme of leucine catabolism'
- term:
    id: GO:1905202
    label: methylcrotonoyl-CoA carboxylase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic inference that MCCC2 is part of the methylcrotonoyl-CoA
      carboxylase complex. MCCC2 (beta) assembles with MCCC1 (alpha) into the alpha6-beta6
      dodecameric holoenzyme.
    action: ACCEPT
    reason: Correct and core. This complex-membership term captures the functional
      unit better than a generic protein binding annotation and is supported by direct
      complex characterization.
    supported_by:
    - reference_id: PMID:17360195
      supporting_text: 'in the recombinant human MCCC, the '
    - reference_id: PMID:11170888
      supporting_text: MCC, an heteromeric enzyme consisting of α (biotin-containing)
        and β subunits
- term:
    id: GO:0004485
    label: methylcrotonoyl-CoA carboxylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (mapped from EC 6.4.1.4 / RHEA:13589 and orthology)
      of the methylcrotonoyl-CoA carboxylase molecular function.
    action: ACCEPT
    reason: The EC/RHEA mapping to GO:0004485 is correct and matches the experimentally
      confirmed catalytic activity. (Note the `enables` qualifier here versus the
      more precise `contributes_to` used elsewhere; the activity is a holoenzyme property.)
    supported_by:
    - reference_id: PMID:17360195
      supporting_text: '74+/-7microM) similar to those reported for the native enzyme.'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation (orthology / UniProtKB-SubCell SL-0170) placing
      MCCC2 in the mitochondrial matrix.
    action: ACCEPT
    reason: Correct and matches direct experimental evidence that MCC is imported
      into and functions in the mitochondrial matrix.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0016874
    label: ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-to-GO electronic annotation of ligase activity, the broad parent
      class of the methylcrotonoyl-CoA carboxylase (carboxylase/ligase) activity.
      EC 6.4.1.4 is a carbon-carbon ligase.
    action: KEEP_AS_NON_CORE
    reason: Not wrong (GO:0004485 is a subclass of GO:0016874, ligase activity), but
      much less informative than the specific carboxylase activity term. Retained
      as a correct parent, marked non-core.
    supported_by:
    - reference_id: PMID:22869039
      supporting_text: 'biotin carboxylase (BC), carboxyltransferase (CT), and'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17360195
  qualifier: enables
  review:
    summary: IPI protein-binding annotation with the MCCC1 alpha subunit (Q96RQ3)
      as the interaction partner. This reflects the physiological intra-holoenzyme
      alpha-beta interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic `protein binding` term is uninformative and does not convey
      the actual function. The biologically meaningful interaction (with MCCC1) is
      captured far better by the methylcrotonoyl-CoA carboxylase complex term (GO:1905202).
      Per curation policy this bare IPI is marked as over-annotated rather than removed.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: MCC, an heteromeric enzyme consisting of α (biotin-containing)
        and β subunits
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27499296
  qualifier: enables
  review:
    summary: IPI protein-binding annotation (MCCC1, Q96RQ3) derived from a large-scale
      mitochondrial protein interaction mapping study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare `protein binding` is uninformative; the relevant interaction with
      the MCCC1 alpha subunit is better represented by the carboxylase complex term
      (GO:1905202). Marked as over-annotated per policy rather than removed.
    supported_by:
    - reference_id: PMID:27499296
      supporting_text: Mitochondrial Protein Interaction Mapping Identifies Regulators
        of Respiratory
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: IPI protein-binding annotation (MCCC1, Q96RQ3) from a proteome-scale
      interactome study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative `protein binding` term; the meaningful MCCC1 interaction
      is captured by GO:1905202. Marked as over-annotated per policy.
    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:35156780
  qualifier: enables
  review:
    summary: IPI protein-binding annotation with CFTR (P13569) recovered from a CFTR-interactome
      mammalian membrane two-hybrid screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic `protein binding`, and the CFTR partner is from a high-throughput
      CFTR-interactome screen with no established biological relationship to this mitochondrial
      matrix metabolic enzyme. Uninformative; marked as over-annotated per policy
      (not removed, as it is an experimental IPI whose full text is not verifiable
      here).
    supported_by:
    - reference_id: PMID:35156780
      supporting_text: CFTR interactome mapping using the mammalian membrane two-hybrid
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36012204
  qualifier: enables
  review:
    summary: IPI protein-binding annotation with CFTR (P13569) from a differential
      CFTR-interactome proximity-labeling study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic, uninformative `protein binding` from a CFTR proximity-labeling
      screen; not indicative of MCCC2's function. Marked as over-annotated per policy.
    supported_by:
    - reference_id: PMID:36012204
      supporting_text: Differential CFTR-Interactome Proximity Labeling Procedures
        Identify Enrichment
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: IPI protein-binding annotation (MCCC1, Q96RQ3) from a multimodal cell-map
      structural/functional genomics study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare `protein binding`; the MCCC1 interaction is better captured by the
      carboxylase complex term. Marked as over-annotated per policy.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional
        genomics
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation (orthology / UniPathway UPA00363) of participation
      in L-leucine catabolism.
    action: ACCEPT
    reason: Correct core biological process, consistent with the pathway assignment
      and experimental evidence.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: 'an enzyme of leucine catabolism'
- term:
    id: GO:0015936
    label: coenzyme A metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic annotation transferred from a rat ortholog assigning coenzyme
      A metabolic process. MCC uses acyl-CoA substrates but does not synthesize, degrade,
      or interconvert coenzyme A itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is a tangential/over-broad mapping. CoA is the carrier scaffold of
      the substrate, not a metabolite processed by MCC; the enzyme carboxylates the
      acyl moiety (leucine catabolism), it does not perform coenzyme A metabolism.
      The accurate process terms are L-leucine / branched-chain amino acid catabolism.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: the enzyme converting 3-methylcrotonoyl-CoA to 3-methylglutaconyl-CoA
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:17360195
  qualifier: located_in
  review:
    summary: Direct assay (ComplexPortal-curated) placing MCCC2 in the mitochondrial
      matrix, the compartment where the MCC holoenzyme functions.
    action: ACCEPT
    reason: Correct and core cellular location, corroborated by mitochondrial import
      studies and multiple independent annotations.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0009083
    label: branched-chain amino acid catabolic process
  evidence_type: NAS
  original_reference_id: PMID:17360195
  qualifier: involved_in
  review:
    summary: Non-traceable author statement that MCCC2 participates in branched-chain
      amino acid catabolism. Leucine is a branched-chain amino acid, so this is the
      broader parent of the L-leucine catabolic process term.
    action: KEEP_AS_NON_CORE
    reason: Correct but less specific than GO:0006552 (L-leucine catabolic process),
      which is a subclass of branched-chain amino acid catabolic process. Retained
      as a valid parent, marked non-core.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: 'an enzyme of leucine catabolism'
- term:
    id: GO:1905202
    label: methylcrotonoyl-CoA carboxylase complex
  evidence_type: IPI
  original_reference_id: PMID:17360195
  qualifier: part_of
  review:
    summary: Interaction-based (ComplexPortal-curated) assignment of MCCC2 as part
      of the methylcrotonoyl-CoA carboxylase complex, based on characterization of
      the assembled alpha/beta enzyme.
    action: ACCEPT
    reason: Correct and core. Captures the functional holoenzyme unit; supported by
      direct purification and characterization of the alpha-beta complex.
    supported_by:
    - reference_id: PMID:17360195
      supporting_text: 'in the recombinant human MCCC, the '
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) localization to the mitochondrion.
    action: ACCEPT
    reason: Correct compartment; consistent with matrix localization. Retained as
      the broader parent of mitochondrial matrix.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: IMP
  original_reference_id: PMID:9544913
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking MCC deficiency to disrupted leucine
      catabolism, from characterization of MCC-deficient Amish/Mennonite adults with
      the diagnostic acylcarnitine/organic-acid profile of impaired leucine degradation.
    action: ACCEPT
    reason: Core biological process supported by loss-of-function/mutant evidence.
      Do not overrule this experimental annotation; the curator had access to the
      full clinical/enzymatic characterization.
    supported_by:
    - reference_id: PMID:9544913
      supporting_text: Isolated 3-methylcrotonyl coenzyme A carboxylase (MCC) deficiency
        was documented
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of MCCC2 in a high-confidence human
      mitochondrial proteome (MitoCoP).
    action: ACCEPT
    reason: Consistent with the well-established mitochondrial (matrix) localization.
      Correct compartment; retained as the broad parent of mitochondrial matrix.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP).
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9909466
  qualifier: located_in
  review:
    summary: Reactome traceable-author-statement placing MCCC2 in the mitochondrial
      matrix (context of the 3-MCC deficiency pathway).
    action: ACCEPT
    reason: Correct and core location, consistent with experimental matrix localization.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:1905202
    label: methylcrotonoyl-CoA carboxylase complex
  evidence_type: IDA
  original_reference_id: PMID:17360195
  qualifier: part_of
  review:
    summary: Direct-assay assignment (ParkinsonsUK-UCL) of MCCC2 as part of the methylcrotonoyl-CoA
      carboxylase complex, from purification/characterization of the assembled enzyme.
    action: ACCEPT
    reason: Correct and core complex-membership annotation, supported by direct characterization
      of the alpha-beta holoenzyme.
    supported_by:
    - reference_id: PMID:17360195
      supporting_text: 'protocol has been developed to purify the active MCCC which
        appears to reside in'
- term:
    id: GO:0004485
    label: methylcrotonoyl-CoA carboxylase activity
  evidence_type: IDA
  original_reference_id: PMID:17360195
  qualifier: contributes_to
  review:
    summary: Direct enzymatic characterization of purified recombinant human MCC establishing
      methylcrotonoyl-CoA carboxylase activity, with measured kinetic parameters (kcat
      ~4.0 s-1; KM ATP 45 uM; KM 3-methylcrotonyl-CoA 74 uM). The `contributes_to`
      qualifier correctly reflects that catalysis is a holoenzyme property to which
      the beta carboxyltransferase subunit contributes.
    action: ACCEPT
    reason: This is the strongest, experimentally demonstrated core molecular function
      of MCCC2. Directly measured activity of the recombinant human enzyme.
    supported_by:
    - reference_id: PMID:17360195
      supporting_text: '74+/-7microM) similar to those reported for the native enzyme.'
- term:
    id: GO:0004485
    label: methylcrotonoyl-CoA carboxylase activity
  evidence_type: NAS
  original_reference_id: PMID:11170888
  qualifier: contributes_to
  review:
    summary: Non-traceable author statement attributing methylcrotonoyl-CoA carboxylase
      activity to the MCC alpha/beta enzyme; the beta subunit provides the acyl-CoA-binding
      carboxyltransferase function.
    action: ACCEPT
    reason: Correct core molecular function; the `contributes_to` qualifier is appropriate
      given the holoenzyme nature of catalysis. Corroborated by the IDA annotation.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: the β subunits contain the binding site for the acyl-CoA substrate
- term:
    id: GO:0004485
    label: methylcrotonoyl-CoA carboxylase activity
  evidence_type: NAS
  original_reference_id: PMID:11181649
  qualifier: contributes_to
  review:
    summary: Non-traceable author statement attributing methylcrotonoyl-CoA carboxylase
      activity to MCC, from the parallel molecular characterization of human MCC deficiency.
    action: ACCEPT
    reason: Correct core molecular function; duplicate support for GO:0004485 with
      the appropriate `contributes_to` qualifier. (Abstract-only cache; deferring to
      the annotating curator, consistent with the well-established enzymology.)
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: the β subunits contain the binding site for the acyl-CoA substrate
- term:
    id: GO:1905202
    label: methylcrotonoyl-CoA carboxylase complex
  evidence_type: NAS
  original_reference_id: PMID:11170888
  qualifier: part_of
  review:
    summary: Non-traceable author statement that MCCC2 (beta) is part of the MCC alpha/beta
      complex.
    action: ACCEPT
    reason: Correct and core; MCC is a heteromeric alpha-beta enzyme and MCCC2 is
      the beta component.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: MCC, an heteromeric enzyme consisting of α (biotin-containing)
        and β subunits
- term:
    id: GO:1905202
    label: methylcrotonoyl-CoA carboxylase complex
  evidence_type: NAS
  original_reference_id: PMID:11181649
  qualifier: part_of
  review:
    summary: Non-traceable author statement that MCCC2 is part of the methylcrotonoyl-CoA
      carboxylase complex.
    action: ACCEPT
    reason: Correct and core complex membership; duplicate support consistent with
      the heteromeric alpha-beta architecture of MCC.
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: MCC, an heteromeric enzyme consisting of α (biotin-containing)
        and β subunits
- term:
    id: GO:1905202
    label: methylcrotonoyl-CoA carboxylase complex
  evidence_type: TAS
  original_reference_id: PMID:22869039
  qualifier: part_of
  review:
    summary: Traceable-author-statement (review of biotin-dependent carboxylase structure/function)
      that MCC is a multi-subunit carboxylase built from biotin carboxylase, carboxyltransferase,
      and biotin-carboxyl-carrier components.
    action: ACCEPT
    reason: Correct and core; MCCC2 is the carboxyltransferase subunit of the MCC
      complex, whose holoenzyme architecture is described in this structural review.
    supported_by:
    - reference_id: PMID:22869039
      supporting_text: 'biotin carboxylase (BC), carboxyltransferase (CT), and'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:11170888
  qualifier: located_in
  review:
    summary: Direct-assay mitochondrial localization consistent with the matrix location
      of the MCC enzyme.
    action: ACCEPT
    reason: Correct compartment; retained as the broad parent of mitochondrial matrix.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IDA
  original_reference_id: PMID:16023992
  qualifier: located_in
  review:
    summary: Direct experimental evidence that MCCbeta is imported into the mitochondrial
      matrix via a cleavable N-terminal targeting presequence (cleavage at Ala22/Tyr23).
    action: ACCEPT
    reason: Strong, direct experimental support for the core matrix localization,
      including definition of the transit peptide.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3065959
  qualifier: located_in
  review:
    summary: Reactome TAS placing MCCC2 in the mitochondrial matrix (carboxylase degradation
      reaction context).
    action: ACCEPT
    reason: Correct core location, consistent with direct experimental matrix localization.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3323111
  qualifier: located_in
  review:
    summary: Reactome TAS placing MCCC2 in the mitochondrial matrix.
    action: ACCEPT
    reason: Correct core location consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-508308
  qualifier: located_in
  review:
    summary: Reactome TAS placing MCCC2 in the mitochondrial matrix (carboxylation
      reaction context).
    action: ACCEPT
    reason: Correct core location; MCC catalyzes its reaction in the matrix.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70773
  qualifier: located_in
  review:
    summary: Reactome TAS placing MCCC2 in the mitochondrial matrix (MCC reaction
      context).
    action: ACCEPT
    reason: Correct core location, consistent with experimental matrix localization.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2993799
  qualifier: located_in
  review:
    summary: Reactome TAS annotating MCCC2 to the cytosol, arising from the modeled
      HLCS-mediated biotinylation / cytosol-to-matrix translocation steps of the nascent
      carboxylase rather than a steady-state functional location.
    action: MARK_AS_OVER_ANNOTATED
    reason: MCCC2 is a matrix enzyme imported via a cleavable presequence; any cytosolic
      presence is a transient import/processing intermediate captured in Reactome's
      biotinylation-and-translocation model, not a site of function. The functional
      localization is the mitochondrial matrix.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3323111
  qualifier: located_in
  review:
    summary: Reactome TAS annotating MCCC2 to the cytosol, from the modeled translocation
      of cytosolic (apo) carboxylases to the mitochondrial matrix.
    action: MARK_AS_OVER_ANNOTATED
    reason: Reflects a transient pre-import state in the Reactome model, not a functional
      cytosolic localization. Mature functional MCC resides in the mitochondrial matrix.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9035987
  qualifier: located_in
  review:
    summary: Reactome TAS annotating MCCC2 to the cytosol, in the context of defective
      HLCS failing to biotinylate the cytosolic apo-carboxylase.
    action: MARK_AS_OVER_ANNOTATED
    reason: A transient pre-import/biotinylation intermediate in the Reactome model
      rather than a functional location. Functional MCC is in the mitochondrial matrix.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: NAS
  original_reference_id: PMID:11181649
  qualifier: located_in
  review:
    summary: Non-traceable author statement of mitochondrial localization for MCCC2.
    action: ACCEPT
    reason: Correct compartment consistent with the established mitochondrial matrix
      localization; retained as the broad parent term.
    supported_by:
    - reference_id: PMID:16023992
      supporting_text: are imported into the mitochondrial matrix by the classical
        pathway involving
- term:
    id: GO:0006552
    label: L-leucine catabolic process
  evidence_type: TAS
  original_reference_id: PMID:11170888
  qualifier: involved_in
  review:
    summary: Traceable-author-statement that MCC (and thus MCCC2) is an enzyme of
      leucine catabolism, with in vivo confirmation via a fungal MCCA-null model.
    action: ACCEPT
    reason: Core biological process, directly supported in the cited paper (including
      a genetic model demonstrating involvement of MCC in leucine catabolism).
    supported_by:
    - reference_id: PMID:11170888
      supporting_text: we use a fungal model for MCG carrying an MCCA null allele,
        to demonstrate, in vivo, the specific involvement of MCC in leucine catabolism
core_functions:
- description: Carboxyltransferase (beta) subunit of mitochondrial 3-methylcrotonyl-CoA
    carboxylase; contributes the methylcrotonoyl-CoA carboxylase activity of the holoenzyme
    by binding the acyl-CoA substrate and accepting the carboxyl group from carboxybiotin
    carried on the MCCC1 alpha subunit, converting 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA.
  molecular_function:
    id: GO:0004485
    label: methylcrotonoyl-CoA carboxylase activity
  directly_involved_in:
  - id: GO:0006552
    label: L-leucine catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  in_complex:
    id: GO:1905202
    label: methylcrotonoyl-CoA carboxylase complex
  supported_by:
  - reference_id: PMID:17360195
    supporting_text: '74+/-7microM) similar to those reported for the native enzyme.'
  - reference_id: PMID:11170888
    supporting_text: the β subunits contain the binding site for the acyl-CoA substrate
proposed_new_terms: []
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11170888
  title: The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine
    catabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text cached and verified. Establishes MCC as a heteromeric
      alpha/beta biotin-dependent carboxylase of leucine catabolism, that the beta
      subunit binds the acyl-CoA substrate, characterizes the human MCCB gene (563-residue
      polypeptide), and demonstrates in vivo involvement of MCC in leucine catabolism
      via a fungal MCCA-null model.
- id: PMID:11181649
  title: The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified title matches; parallel molecular characterization
      of human MCC deficiency and MCCC2 disease variants. Cache is abstract-only;
      claims (carboxylase activity, complex membership) are consistent with the well-established
      enzymology and corroborated by the IDA evidence.
- id: PMID:16023992
  title: Mitochondrial targeting signals and mature peptides of 3-methylcrotonyl-CoA
    carboxylase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-cached; directly supports mitochondrial matrix import of
      MCCbeta via a cleavable N-terminal presequence (cleavage Ala22/Tyr23), grounding
      the matrix localization annotations.
- id: PMID:17360195
  title: Expression, purification, characterization of human 3-methylcrotonyl-CoA
    carboxylase (MCCC).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-cached. Direct enzymatic characterization of purified recombinant
      human MCC (alpha/beta complex, ~500-800 kDa, 1:1 stoichiometry, kcat ~4.0 s-1,
      KM values), grounding the carboxylase-activity and complex-membership annotations.
- id: PMID:22869039
  title: Structure and function of biotin-dependent carboxylases.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review of biotin-dependent carboxylase structure/function; supports
      the multi-subunit (BC/CT/BCCP) architecture of MCC and the carboxyltransferase
      role of the beta subunit.
- id: PMID:27499296
  title: Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory
    Chain Function.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale mitochondrial interaction mapping; the MCCC2-MCCC1 interaction
      it captures is real but only supports a generic protein-binding annotation better
      represented by the carboxylase complex term.
- 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 generic protein-binding
      IPI (MCCC1). Contextual, not function-establishing for MCCC2.
- 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 (MitoCoP); corroborates mitochondrial
      localization of MCCC2 by high-throughput proteomics.
- id: PMID:35156780
  title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput
    screening system.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput CFTR-interactome screen; the CFTR-MCCC2 IPI has
      no established biological relationship to this matrix enzyme and is likely non-specific.
- id: PMID:36012204
  title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment
    in Multiple SLC Transporters.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: CFTR proximity-labeling screen; source of a generic CFTR-MCCC2 protein-binding
      IPI, not indicative of MCCC2 function.
- 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 study; source of a generic protein-binding
      IPI (MCCC1). Contextual.
- id: PMID:9544913
  title: 3-Methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonite adults
    identified by detection of increased acylcarnitines in blood spots of their children.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-cached. Documents isolated MCC deficiency in humans, underpinning
      the IMP link between loss of MCC and disrupted leucine catabolism.
- id: Reactome:R-HSA-2993799
  title: HLCS biotinylates 6xMCCC1:6xMCCC2
  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-508308
  title: beta-methylglutaconyl-CoA + ADP + orthophosphate <=> beta-methylcrotonyl-CoA
    + ATP + HCO3- (MCCA)
  findings: []
- id: Reactome:R-HSA-70773
  title: beta-methylcrotonyl-CoA + ATP + HCO3- <=> beta-methylglutaconyl-CoA + ADP
    + orthophosphate + H2O (MCCA)
  findings: []
- id: Reactome:R-HSA-9035987
  title: Defective HLCS does not biotinylate 6xMCCC1:6xMCCC2
  findings: []
- id: Reactome:R-HSA-9909466
  title: MCCC mutants don't synthesize beta-methylglutaconyl-CoA
  findings: []