id: Q8IVH4
gene_symbol: MMAA
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MMAA (methylmalonic aciduria type A protein; the human cblA protein) is a mitochondrial
  GTPase of the SIMIBI-class G3E GTPase family, ArgK/MeaB subfamily (Pfam MeaB;
  InterPro GTPase_ArgK). It is imported into the mitochondrial matrix via a cleaved
  N-terminal transit peptide and functions as a G-protein chaperone that assists delivery
  and maintenance of the adenosylcobalamin (AdoCbl, vitamin B12) cofactor for the enzyme
  methylmalonyl-CoA mutase (MMUT/MUT). MMAA itself is not the mutase and does not isomerize
  methylmalonyl-CoA; instead, in a GTP-binding- and GTP-hydrolysis-dependent manner it gates
  the transfer of AdoCbl from the adenosyltransferase MMAB onto MMUT apoenzyme, protects the
  MMUT-bound cofactor from oxidative inactivation, and reactivates MMUT by promoting exchange
  of the damaged cofactor. Its low intrinsic GTPase activity is strongly stimulated by MMUT
  (which acts as a GAP), and MMAA forms a homodimer that assembles into nucleotide-sensitive
  interconverting oligomeric complexes with MMUT. Loss-of-function variants cause
  methylmalonic aciduria, cblA type (MACA), an autosomal recessive disorder of B12/AdoCbl
  metabolism that is frequently vitamin-B12(hydroxocobalamin)-responsive.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (PAN-GO) inference placing MMAA activity in the cytoplasm. MMAA is
      synthesized with a mitochondrial transit peptide and is imported into the
      mitochondrial matrix where it performs its chaperone/GTPase function on MMUT.
      Cytoplasmic/cytosolic detection is real (precursor pool / partial import), but the
      core functional compartment is the mitochondrial matrix, not the general cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: >-
      The gene product has a cleaved mitochondrial transit peptide and colocalizes with MMUT
      in mitochondria, so "cytoplasm" is not the core functional location; retain as a
      non-core localization signal rather than the primary site of action.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        for the first time, the in vivo localization of hMMAA and its colocalization with
        hMCM in human fibroblasts mitochondria were demonstrated
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      GTPase activity is the central, phylogenetically conserved molecular function of MMAA
      and its ArgK/MeaB-subfamily orthologs. Directly demonstrated for the human protein and
      consistent with the conserved P-loop G-domain.
    action: ACCEPT
    reason: >-
      Core molecular function; IBA is concordant with multiple experimental (IDA/IMP)
      annotations and with structural characterization of the GDP-bound protein.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: We show that MMAA exhibits GTPase activity that is modulated by MUT
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (ARBA/InterPro/RHEA) assignment of GTPase activity mapped from the
      GTPase_ArgK domain and the GTP hydrolysis reaction (RHEA:19669). Correct.
    action: ACCEPT
    reason: >-
      Electronic assignment agrees with the experimentally verified GTPase activity and the
      UniProt-annotated catalytic reaction GTP + H2O = GDP + phosphate + H(+).
    supported_by:
    - reference_id: PMID:28497574
      supporting_text: This function of MMAA depends on its GTPase activity
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO mapping of GTP binding from the GTPase_ArgK domain. MMAA binds GTP/GDP
      (crystallized in the GDP-bound form; defined GTP-binding loops), so this is correct.
    action: ACCEPT
    reason: >-
      GTP binding is directly demonstrated experimentally and is an intrinsic property of the
      G-domain; electronic assignment is appropriate.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: Formation of a stable MMAA-MUT complex is nucleotide-selective for MMAA
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic mapping from the UniProt Subcellular Location "Cytoplasm" keyword. MMAA is
      detected in the cytoplasm but its core functional site is the mitochondrial matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the curated UniProt subcellular location; kept as a non-core
      localization since the protein functions after mitochondrial import.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic mapping from the UniProt Subcellular Location "Mitochondrion" keyword. This
      is the core functional compartment of MMAA.
    action: ACCEPT
    reason: >-
      Agrees with experimental (IDA/HTP) localization and with the presence of a cleaved
      mitochondrial transit peptide.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20876572
  qualifier: enables
  review:
    summary: >-
      IntAct-curated interaction with MMUT (UniProtKB:P22033). The biologically meaningful
      interaction is the GTP-dependent MMAA-MMUT complex through which AdoCbl is delivered;
      the bare "protein binding" term is uninformative about this function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidance, generic "protein binding" is uninformative; the specific
      MMAA-MMUT interaction is better captured by the chaperone/complex-formation role and by
      the identical/homodimerization terms. Retained (not removed) as it records a real,
      experimentally supported interaction with MMUT.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: the two proteins interact in vitro and in vivo
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28497574
  qualifier: enables
  review:
    summary: >-
      IntAct-curated interaction with MMUT (UniProtKB:P22033). As above, "protein binding" is
      uninformative; the functionally relevant interaction is the GTPase-stimulating,
      AdoCbl-gating MMAA-MMUT complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein-binding term over-annotates a specific, functionally important
      MMAA-MMUT interaction; kept as a real interaction record rather than removed.
    supported_by:
    - reference_id: PMID:28497574
      supporting_text: >-
        This function of MMAA depends on its GTPase activity, which is stimulated by an
        interaction with MUT
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20876572
  qualifier: enables
  review:
    summary: >-
      Self-interaction (homodimer) supported by IntAct and by the crystal structure, in which
      MMAA is an alpha2 homodimer.
    action: ACCEPT
    reason: >-
      The homodimeric state is structurally and biochemically verified and is relevant to the
      protein's oligomerization behavior with MMUT.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: >-
        yet they show substantially different dimeric assembly and interaction, compared with
        their bacterial counterparts
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759218
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable assertion placing MMAA in cobalamin (vitamin B12) metabolism. MMAA
      is required for intracellular handling of B12, specifically the mitochondrial delivery
      and maintenance of the AdoCbl cofactor on MMUT.
    action: ACCEPT
    reason: >-
      Core biological process; consistent with experimental (IDA) annotations and with the
      cblA-type methylmalonic aciduria disease mechanism (reduced mitochondrial AdoCbl pool).
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: >-
        MMAA (methylmalonic aciduria type A), is implicated in the mitochondrial assembly of
        AdoCbl into MUT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (Human Protein Atlas) detection in the cytosol. MMAA is synthesized
      as a cytosolic precursor and imported into mitochondria; the functionally relevant
      pool is mitochondrial.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real immunofluorescence localization but not the core site of function; the protein
      acts in the mitochondrial matrix after transit-peptide cleavage.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteomics detected MMAA in the mitochondrion,
      corroborating its curated mitochondrial localization.
    action: ACCEPT
    reason: >-
      Consistent with the core mitochondrial localization established by targeted
      immunofluorescence and by the cleaved mitochondrial transit peptide.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3159259
  qualifier: enables
  review:
    summary: >-
      Reactome TAS ("MMAA:MUT binds AdoCbl") assigning molecular carrier activity. MMAA does
      not itself carry cobalamin as cargo; it is the G-protein that gates the transfer of
      AdoCbl (produced by MMAB) onto MMUT in a GTP-dependent manner. "Molecular carrier
      activity" mislabels the gating/regulatory GTPase role as direct cofactor transport.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The precise molecular function is GTPase activity; the AdoCbl delivery is a gated
      protein-protein handoff between MMAB and MUT that MMAA regulates rather than a carrier
      activity that MMAA itself enables. Retained (not removed) because MMAA is genuinely
      required for cofactor delivery, but flagged as over-annotated at the MF level.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: >-
        our data point to a gatekeeping role for MMAA by favoring complex formation with MUT
        apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the
        complex, in a GTP-dependent manner
    - reference_id: PMID:28497574
      supporting_text: >-
        all mutations interfered with gating the transfer of AdoCbl from MMAB to MUT
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:31056463
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Direct assay showing MMAA (CblA) allosterically regulates AdoCbl movement to/from MMUT;
      patient cblA mutations reduce the mitochondrial AdoCbl pool, placing MMAA upstream of or
      within cobalamin/AdoCbl metabolism.
    action: ACCEPT
    reason: >-
      Experimentally supported role in the mitochondrial B12/AdoCbl trafficking pathway; core
      biological process for MMAA.
    supported_by:
    - reference_id: PMID:31056463
      supporting_text: 'chaperone CblA is transduced via three "switch" elements that gate the movement'
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: IDA
  original_reference_id: PMID:31056463
  qualifier: enables
  review:
    summary: >-
      IDA (MGI) assigning molecular carrier activity from the allosteric-oligomerization
      study. As with the Reactome annotation, MMAA gates B12 movement between MMAB and MMUT
      via its GTPase rather than acting as a direct molecular carrier of the cofactor.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The paper demonstrates GTPase-gated cofactor movement and oligomer regulation, not a
      carrier/transport activity intrinsic to MMAA; the informative MF is GTPase activity.
      Kept as a record of the cofactor-movement role but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:31056463
      supporting_text: >-
        gate the movement of the B12 cofactor to and from MCM
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:31056463
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental involvement in cobalamin/AdoCbl metabolism: MMAA (CblA) gates B12
      cofactor movement to/from MMUT, and cblA mutations lower the fibroblast AdoCbl pool.
    action: ACCEPT
    reason: >-
      Core biological process supported by direct measurements of AdoCbl pool depletion in
      cblA patient cells and by the gating mechanism.
    supported_by:
    - reference_id: PMID:31056463
      supporting_text: >-
        AdoCbl represents 15.1
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:21138732
  qualifier: enables
  review:
    summary: >-
      Direct assay of purified recombinant human MMAA showing GTP-hydrolysis-dependent
      reactivation of methylmalonyl-CoA mutase, demonstrating functional GTPase activity.
    action: ACCEPT
    reason: >-
      Core molecular function, directly demonstrated; MMAA reactivates inactive mutase via
      GTP hydrolysis.
    supported_by:
    - reference_id: PMID:21138732
      supporting_text: >-
        the addition of MMAA increases the enzymatic activity through GTP hydrolysis,
        indicating reactivation of MCM by exchange of the damaged cofactor
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:28943303
  qualifier: enables
  review:
    summary: >-
      Direct assay showing MMAA removes the damaged (oxidized) cofactor from inactive mutase
      through GTP hydrolysis, confirming functional GTPase activity.
    action: ACCEPT
    reason: >-
      Core molecular function; directly demonstrated GTP-hydrolysis-coupled cofactor exchange.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: hMMAA is able to remove the damaged cofactor through GTP hydrolysis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21138732
  qualifier: enables
  review:
    summary: >-
      Interaction with MMUT (UniProtKB:P22033) confirmed by yeast two-hybrid. The
      functionally relevant interaction is the MMAA-MMUT chaperone complex; "protein binding"
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein-binding term over-annotates the specific, experimentally verified
      MMAA-MMUT interaction; retained (not removed) as a real interaction.
    supported_by:
    - reference_id: PMID:21138732
      supporting_text: >-
        Interaction between MCM and MMAA observed in vitro was confirmed in vivo by yeast
        two-hybrid system
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28943303
  qualifier: enables
  review:
    summary: >-
      Interaction with MMUT (UniProtKB:P22033). As above, the informative description is the
      MMAA-MMUT complex through which cofactor protection/exchange occurs, not bare "protein
      binding".
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative generic term; the specific MMAA-MMUT complex is better captured elsewhere.
      Kept as a real, experimentally supported interaction.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        restores methylmalonyl-CoA mutase activity through their complex formation
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:28943303
  qualifier: located_in
  review:
    summary: >-
      Direct localization detected MMAA in the cytoplasm in addition to mitochondria. The
      protein's core functional pool is mitochondrial (matrix), consistent with its transit
      peptide and MMUT colocalization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real localization but not the core functional compartment; MMAA acts on MMUT after
      mitochondrial import.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:28943303
  qualifier: located_in
  review:
    summary: >-
      Direct in vivo demonstration that MMAA localizes to and colocalizes with MMUT in human
      fibroblast mitochondria. This is the core functional compartment.
    action: ACCEPT
    reason: >-
      Core cellular localization, directly demonstrated and consistent with the cleaved
      mitochondrial transit peptide.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:20876572
  qualifier: enables
  review:
    summary: >-
      Structural and biochemical study directly demonstrating that human MMAA is a GTPase
      whose activity is modulated by MMUT; crystallized in the GDP-bound form.
    action: ACCEPT
    reason: >-
      Core molecular function, directly demonstrated with structural support (PDB 2WWW).
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: We show that MMAA exhibits GTPase activity that is modulated by MUT
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IMP
  original_reference_id: PMID:28497574
  qualifier: enables
  review:
    summary: >-
      Mutational analysis of 15 purified MACA mutant proteins showed wild-type-like intrinsic
      GTPase activity for all but the GTP-binding-domain variant, confirming GTPase activity
      as an intrinsic MMAA function and dissecting the MUT-stimulated (GAP) component.
    action: ACCEPT
    reason: >-
      Core molecular function; IMP evidence corroborates the intrinsic GTPase activity and its
      MUT-dependent stimulation.
    supported_by:
    - reference_id: PMID:28497574
      supporting_text: >-
        All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:20876572
  qualifier: enables
  review:
    summary: >-
      Direct demonstration of GTP/GDP binding by human MMAA, crystallized in the GDP-bound
      form with defined GTP-binding loops; complex formation with MMUT is nucleotide-selective.
    action: ACCEPT
    reason: >-
      GTP binding is directly demonstrated and structurally characterized; intrinsic property
      of the G-domain.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: Formation of a stable MMAA-MUT complex is nucleotide-selective for MMAA
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:28497574
  qualifier: enables
  review:
    summary: >-
      Direct assays of GTP/GDP binding across MACA mutants; only the GTP-binding-domain
      variant (p.Asp292Val) showed decreased GTP binding, confirming GTP binding as an
      intrinsic MMAA property.
    action: ACCEPT
    reason: >-
      GTP binding directly demonstrated; consistent with the conserved G-domain.
    supported_by:
    - reference_id: PMID:28497574
      supporting_text: >-
        only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed
        decreased GTP binding
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: TAS
  original_reference_id: PMID:28497574
  qualifier: involved_in
  review:
    summary: >-
      MMAA regulates incorporation of the AdoCbl cofactor into MMUT, placing it in
      cobalamin/AdoCbl metabolism; cblA mutations impair AdoCbl transfer and cause disease.
    action: ACCEPT
    reason: >-
      Core biological process; strongly supported by the mechanistic and disease-variant data.
    supported_by:
    - reference_id: PMID:28497574
      supporting_text: >-
        MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl),
        generated from the MMAB adenosyltransferase, into the destination enzyme
        methylmalonyl-CoA mutase (MUT)
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:20876572
  qualifier: enables
  review:
    summary: >-
      Direct structural demonstration that MMAA self-associates as a homodimer (alpha2),
      distinct from its bacterial counterparts.
    action: ACCEPT
    reason: >-
      Homodimerization is structurally verified and relevant to MMAA oligomerization behavior.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: >-
        yet they show substantially different dimeric assembly and interaction, compared with
        their bacterial counterparts
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:20876572
  qualifier: enables
  review:
    summary: >-
      MMAA forms a homodimer, directly demonstrated in the crystal structure. This
      self-association underlies its nucleotide-sensitive oligomerization with MMUT.
    action: ACCEPT
    reason: >-
      Homodimerization activity is directly and structurally supported; a genuine, specific
      molecular property.
    supported_by:
    - reference_id: PMID:20876572
      supporting_text: >-
        yet they show substantially different dimeric assembly and interaction, compared with
        their bacterial counterparts
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322135
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS placing MMAA in the mitochondrial matrix (the "Defective MMAA does not
      protect MUT" reaction). This is the specific compartment where MMAA acts on MMUT.
    action: ACCEPT
    reason: >-
      Consistent with the cleaved mitochondrial transit peptide, matrix-localized MMUT, and
      the demonstrated mitochondrial colocalization; the most precise functional location.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3159259
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS placing MMAA in the mitochondrial matrix (the "MMAA:MUT binds AdoCbl"
      reaction). Correct core functional location.
    action: ACCEPT
    reason: >-
      Matrix localization is consistent with mitochondrial import and MMUT colocalization.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322971
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS placing MMAA in the mitochondrial matrix. Consistent with its functional
      compartment.
    action: ACCEPT
    reason: >-
      Matrix localization is well supported; core functional location.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71010
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS placing MMAA in the mitochondrial matrix (associated with the MUT
      isomerization reaction module). Consistent with the functional compartment.
    action: ACCEPT
    reason: >-
      Matrix localization is well supported by import signal and MMUT colocalization.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the in vivo localization of hMMAA and its colocalization with hMCM in human
        fibroblasts mitochondria were demonstrated
- term:
    id: GO:0043085
    label: positive regulation of catalytic activity
  evidence_type: IDA
  original_reference_id: PMID:21138732
  qualifier: involved_in
  review:
    summary: >-
      MMAA reactivates inactive methylmalonyl-CoA mutase and protects it from inactivation,
      thereby positively regulating the catalytic activity of MMUT. This chaperone/reactivase
      role is well documented but is not captured by the existing GOA terms.
    action: NEW
    reason: >-
      Proposed new annotation capturing MMAA's protectase/reactivase function toward MMUT,
      demonstrated in vitro with purified proteins. Supports the corresponding core function.
    supported_by:
    - reference_id: PMID:21138732
      supporting_text: >-
        the addition of MMAA increases the enzymatic activity through GTP hydrolysis,
        indicating reactivation of MCM by exchange of the damaged cofactor
    - reference_id: PMID:28943303
      supporting_text: >-
        restores methylmalonyl-CoA mutase activity through their complex formation
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:28943303
  qualifier: involved_in
  review:
    summary: >-
      By forming a complex with MMUT, MMAA slows formation of the oxidized inactive cofactor
      (OH2Cbl) and thereby protects/maintains functional MMUT, i.e. stabilizes the active
      holoenzyme. Documented mechanistically but not present in the existing GOA set.
    action: NEW
    reason: >-
      Proposed new annotation capturing MMAA's protective (protectase) role toward MMUT;
      supports the corresponding core function.
    supported_by:
    - reference_id: PMID:28943303
      supporting_text: >-
        the complex formation of hMCM/hMMAA decreases the rate of oxidized cofactor
        formation, protecting the hMCM enzyme
    - reference_id: PMID:21138732
      supporting_text: >-
        it prevents inactivation by guarding MCM
core_functions:
- description: >-
    Mitochondrial matrix GTPase that binds and hydrolyzes GTP; its low intrinsic GTPase
    activity is strongly stimulated by methylmalonyl-CoA mutase (MMUT/MUT), which acts as a
    GAP. This nucleotide cycle powers MMAA's chaperone functions toward MMUT.
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  directly_involved_in:
  - id: GO:0009235
    label: cobalamin metabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:20876572
    supporting_text: We show that MMAA exhibits GTPase activity that is modulated by MUT
  - reference_id: PMID:28497574
    supporting_text: >-
      This function of MMAA depends on its GTPase activity, which is stimulated by an
      interaction with MUT
- description: >-
    G-protein chaperone that, in a GTP-dependent manner, gates transfer of the
    adenosylcobalamin (AdoCbl) cofactor from the adenosyltransferase MMAB onto MMUT
    apoenzyme, protects the MMUT-bound cofactor from oxidative inactivation, and reactivates
    inactive MMUT by promoting exchange of the damaged cofactor. This maintains MMUT (and
    hence propionate/methylmalonyl-CoA) flux and is the process disrupted in cblA-type
    methylmalonic aciduria. MMAA is not itself the mutase and does not carry the cofactor as
    cargo; it regulates a gated protein-protein handoff.
  molecular_function:
    id: GO:0003924
    label: GTPase activity
  directly_involved_in:
  - id: GO:0009235
    label: cobalamin metabolic process
  - id: GO:0043085
    label: positive regulation of catalytic activity
  - id: GO:0050821
    label: protein stabilization
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:20876572
    supporting_text: >-
      our data point to a gatekeeping role for MMAA by favoring complex formation with MUT
      apoenzyme for AdoCbl assembly and releasing the AdoCbl-loaded holoenzyme from the
      complex, in a GTP-dependent manner
  - reference_id: PMID:21138732
    supporting_text: >-
      it prevents inactivation by guarding MCM
  - reference_id: PMID:28943303
    supporting_text: >-
      the complex formation of hMCM/hMMAA decreases the rate of oxidized cofactor formation,
      protecting the hMCM enzyme
proposed_new_terms: []
suggested_questions:
- question: >-
    Is MMAA best described at the molecular-function level by a dedicated cofactor-loading /
    GTPase-dependent chaperone term rather than the generic "molecular carrier activity",
    given that it gates a protein-protein cofactor handoff rather than transporting cobalamin
    itself?
- question: >-
    What is the physiological significance of the cytoplasmic/cytosolic MMAA pool detected by
    immunofluorescence and proteomics, versus the functionally characterized mitochondrial
    matrix pool?
suggested_experiments:
- description: >-
    Reconstitute the full human mitochondrial B12 pathway (MMAB/ATR, MMAA/CblA, MMUT) in
    vitro and use single-turnover/stopped-flow spectroscopy to quantify how GTP binding vs
    hydrolysis by MMAA controls the directionality of AdoCbl loading and cob(II)alamin
    offloading.
- description: >-
    Use cryo-EM of the nucleotide-sensitive MMAA-MMUT oligomers to define the loading-ready
    state and map how cblA switch-region patient variants shift the oligomeric equilibrium.
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:20876572
  title: Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA
    mutase and insight into their complex formation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Structural/biochemical study establishing MMAA as a GTPase modulated
      by MUT, homodimer (PDB 2WWW), and its GTP-dependent gatekeeping role for AdoCbl assembly
      into MUT.
- id: PMID:21138732
  title: Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Demonstrates MMAA's dual protectase/reactivase role toward MCM and the
      GTP-hydrolysis-dependent cofactor exchange.
- id: PMID:28497574
  title: Protein destabilization and loss of protein-protein interaction are fundamental
    mechanisms in cblA-type methylmalonic aciduria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Large patient/mutant series showing intrinsic GTPase is retained while
      MUT-stimulated GTPase, MUT binding, and AdoCbl gating are lost in disease variants.
- id: PMID:28943303
  title: Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA
    mutase activity through their complex formation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Shows OH2Cbl accumulation causes MCM inactivation, MMAA complex slows
      this, and MMAA removes the damaged cofactor via GTP hydrolysis; first in vivo mito
      colocalization of hMMAA with hMCM.
- id: PMID:31056463
  title: Allosteric Regulation of Oligomerization by a B(12) Trafficking G-Protein
    Is Corrupted in Methylmalonic Aciduria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified, full text available. Human MCM-CblA form nucleotide-sensitive
      interconverting oligomers; GTPase-driven resolution to the loading-ready state is
      needed for AdoCbl loading; cblA switch III mutations reduce the fibroblast AdoCbl pool.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Large-scale mitochondrial proteomics; corroborates mitochondrial
      localization of MMAA but does not directly address molecular function.
- id: Reactome:R-HSA-3159259
  title: MMAA:MUT binds AdoCbl
  findings: []
- id: Reactome:R-HSA-3322135
  title: Defective MMAA does not protect MUT
  findings: []
- id: Reactome:R-HSA-3322971
  title: Defective MUT does not isomerise L-MM-CoA to SUCC-CoA
  findings: []
- id: Reactome:R-HSA-71010
  title: MUT isomerises L-MM-CoA to SUCC-CoA
  findings: []
- id: Reactome:R-HSA-9759218
  title: Cobalamin (Cbl) metabolism
  findings: []