id: Q9H3L0
gene_symbol: MMADHC
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MMADHC (cobalamin trafficking protein CblD; the cblD complementation group) is a
  cobalamin (vitamin B12)-trafficking branch-point/adaptor protein. It acts downstream of
  MMACHC (cblC) in the cytosol, where it physically associates with MMACHC and, together
  with methionine synthase (MTR) and methionine synthase reductase (MTRR), directs the
  common cob(II)alamin intermediate into one of two coenzyme-synthesis branches: the
  mitochondrial adenosylcobalamin (AdoCbl) branch that supplies methylmalonyl-CoA mutase
  (MMUT), or the cytosolic methylcobalamin (MeCbl) branch that supplies methionine synthase
  (MTR). MMADHC is not an enzyme; its C-terminal domain adopts a nitro-FMN-reductase-like
  fold and provides a cysteine (Cys261) thiolate ligand to cob(II)alamin bound to MMACHC.
  The protein has both cytosolic and mitochondrial pools and carries a predicted N-terminal
  mitochondrial transit peptide. Distinct mutation positions determine which branch fails,
  producing three biochemical phenotypes: isolated methylmalonic aciduria (cblD-variant 2),
  isolated homocystinuria (cblD-variant 1), or combined methylmalonic aciduria and
  homocystinuria.
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. MMADHC has a predicted
      N-terminal mitochondrial transit peptide and a documented mitochondrial pool in
      addition to its cytosolic pool, consistent with its role in routing cobalamin
      toward the mitochondrial AdoCbl branch.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localization is supported experimentally (IDA/HTP) and by the UniProt
      transit peptide annotation, so the IBA localization is biologically correct. However,
      the functionally decisive branch-point/adaptor activity occurs in the cytosol
      (downstream of MMACHC, in complex with MMACHC/MTR/MTRR); the mitochondrial pool is a
      secondary compartment, hence retained as non-core.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
    - reference_id: file:human/MMADHC/MMADHC-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:23270877}.
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred involvement in cobalamin metabolism. This is the central,
      well-supported biological process for MMADHC: it acts as a branch point directing
      cobalamin into the AdoCbl (mitochondrial) and MeCbl (cytosolic) coenzyme pathways.
    action: ACCEPT
    reason: >-
      Strongly corroborated by multiple experimental studies establishing MMADHC as a
      cobalamin-trafficking branch-point protein downstream of MMACHC. Represents a core
      biological process for this gene.
    supported_by:
    - reference_id: PMID:22156578
      supporting_text: supporting the role of cblD protein as a branch point in
    - reference_id: PMID:23270877
      supporting_text: MMADHC acts as a branch point for vitamin B(12) delivery to
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred molecular carrier activity. MMADHC is a non-enzymatic
      cobalamin-trafficking adaptor that receives/hands off the cobalamin cofactor
      (partitioning it between the MeCbl and AdoCbl branches) rather than catalyzing a
      chemical reaction. Molecular carrier activity captures this carrier/adaptor role.
    action: ACCEPT
    reason: >-
      Consistent with the multiple independent IDA/EXP/TAS annotations to the same term and
      with the biochemical evidence that MMADHC functions as an adaptor controlling
      intracellular cobalamin partitioning rather than as an enzyme. This is the best
      available molecular-function term for a non-catalytic cofactor-trafficking protein.
    supported_by:
    - reference_id: PMID:23415655
      supporting_text: an adapter function for CblD
    - reference_id: PMID:22156578
      supporting_text: supporting the role of cblD protein as a branch point in
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniProt SubCell mapping) annotation to cytoplasm. Consistent with the
      documented cytoplasmic pool of MMADHC, where its branch-point/adaptor activity occurs.
    action: ACCEPT
    reason: >-
      Correct but general; the more specific experimentally supported cytosol term
      (GO:0005829) is also annotated. Accept as a valid, if broad, localization.
    supported_by:
    - reference_id: file:human/MMADHC/MMADHC-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:23270877}.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniProt SubCell mapping) annotation to mitochondrion, matching the
      predicted N-terminal mitochondrial transit peptide and the experimentally observed
      mitochondrial pool.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localization is real and supported (transit peptide; IDA; HTP), but
      secondary to the cytosolic branch-point activity, so kept as non-core.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation (IPR019362, the MMADHC family) to cobalamin
      metabolic process. The InterPro family is specific to this cobalamin-trafficking
      protein, so the mapping is accurate.
    action: ACCEPT
    reason: >-
      Correct biological process, redundant with the well-supported IBA/IDA annotations to
      the same term. Represents a core process.
    supported_by:
    - reference_id: PMID:22156578
      supporting_text: supporting the role of cblD protein as a branch point in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare protein binding from a large-scale binary interactome map (HuRI), with
      high-throughput yeast two-hybrid interactors (CREB5, POU4F2, TBC1D7, CINP) that are
      not part of the established cobalamin-trafficking machinery and are of unclear
      biological relevance to MMADHC function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidance, bare "protein binding" is uninformative and this comes from a
      genome-scale two-hybrid screen whose hits are not the biologically meaningful partners
      (MMACHC, MTR, MTRR). Not removed (experimental IPI), but marked as over-annotated; the
      informative partners are captured by the molecular carrier activity and cobalamin
      metabolic process terms.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        we present a human 'all-by-all' reference interactome map of human binary protein
        interactions, or 'HuRI'.
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759218
  qualifier: involved_in
  review:
    summary: >-
      Reactome pathway annotation (Cobalamin metabolism) placing MMADHC in cobalamin
      metabolic process. Consistent with all other evidence for this gene.
    action: ACCEPT
    reason: >-
      Traceable author statement from Reactome for a core biological process; concordant
      with the IBA/IDA/IEA annotations to the same term.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC acts as a branch point for vitamin B(12) delivery to
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput detection of MMADHC in a high-confidence human mitochondrial proteome,
      corroborating the mitochondrial pool identified by immunofluorescence/fractionation
      and the predicted mitochondrial transit peptide.
    action: KEEP_AS_NON_CORE
    reason: >-
      Confirms mitochondrial localization but this compartment is secondary to the cytosolic
      branch-point activity; kept as non-core localization.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: high-confidence human mitochondrial proteome
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149563
  qualifier: enables
  review:
    summary: >-
      Reactome TAS annotation (MMADHC targets transport of cytosolic cob(II)alamin to
      mitochondria) to molecular carrier activity, capturing MMADHC's cobalamin
      carrier/routing role.
    action: ACCEPT
    reason: >-
      Consistent with the branch-point/adaptor function; molecular carrier activity is the
      appropriate non-enzymatic MF term. Redundant with the IBA/IDA/EXP annotations to the
      same term.
    supported_by:
    - reference_id: PMID:23415655
      supporting_text: an adapter function for CblD
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: EXP
  original_reference_id: PMID:21071249
  qualifier: enables
  review:
    summary: >-
      Experimental support (via Reactome) for cobalamin carrier/adaptor activity, based on
      the demonstrated direct interaction of MMADHC with MMACHC, the partner that hands off
      the cobalamin cofactor.
    action: ACCEPT
    reason: >-
      The MMACHC-MMADHC interaction underpins MMADHC's role as a downstream cobalamin
      carrier/adaptor; molecular carrier activity is the correct MF term.
    supported_by:
    - reference_id: PMID:21071249
      supporting_text: MMADHC was confirmed as a binding
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:23270877
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (immunofluorescence and subcellular fractionation) localization of
      MMADHC to the cytosol, the compartment where it acts downstream of MMACHC as a
      cobalamin branch point.
    action: ACCEPT
    reason: >-
      Well-supported specific cytosolic localization; this is the primary site of MMADHC's
      branch-point/adaptor activity and is retained as a core location.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:22156578
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Direct experimental evidence (complementation of cblD patient fibroblasts; mutation
      position correlating with biochemical phenotype) that MMADHC acts within cobalamin
      metabolism as a branch point balancing cytosolic MeCbl and mitochondrial AdoCbl
      synthesis.
    action: ACCEPT
    reason: >-
      Core biological process, directly demonstrated. The acts_upstream_of_or_within
      qualifier reflects the regulatory branch-point role.
    supported_by:
    - reference_id: PMID:22156578
      supporting_text: supporting the role of cblD protein as a branch point in
    - reference_id: PMID:22156578
      supporting_text: correlate with the biochemical phenotype
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: IDA
  original_reference_id: PMID:22156578
  qualifier: enables
  review:
    summary: >-
      Direct experimental support for MMADHC's cobalamin carrier/branch-point activity:
      a single protein with two functional domains that partition cobalamin between the
      cytosolic MeCbl and mitochondrial AdoCbl routes.
    action: ACCEPT
    reason: >-
      Molecular carrier activity is the appropriate non-enzymatic MF term for this
      cofactor-partitioning adaptor; directly supported by the phenotype/rescue data.
    supported_by:
    - reference_id: PMID:22156578
      supporting_text: supporting the role of cblD protein as a branch point in
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: IDA
  original_reference_id: PMID:32871076
  qualifier: enables
  review:
    summary: >-
      Direct experimental evidence that CblD/MMADHC provides a Cys261 thiolate ligand to
      cob(II)alamin bound to CblC/MMACHC, forming an interprotein Co-S coordination complex
      used for cofactor translocation in the trafficking pathway - a molecular carrier/handoff
      activity.
    action: ACCEPT
    reason: >-
      Biochemical/structural demonstration of direct cobalamin coordination by MMADHC in the
      trafficking pathway strongly supports molecular carrier activity as its MF.
    supported_by:
    - reference_id: PMID:32871076
      supporting_text: CblD provides a sulfur ligand to cob(II)alamin bound to CblC
    - reference_id: PMID:32871076
      supporting_text: Cys-261 on CblD as the sulfur donor
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:23270877
  qualifier: is_active_in
  review:
    summary: >-
      Direct experimental evidence that MMADHC is active in the cytosol, where it functions
      downstream of MMACHC as the cobalamin branch point (and in complex with MMACHC, MTR
      and MTRR).
    action: ACCEPT
    reason: >-
      Cytosol is the primary site of MMADHC's branch-point/adaptor activity; the is_active_in
      qualifier is appropriate and this is a core location for the molecular function.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:22156578
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental involvement in cobalamin metabolic process (branch-point control
      of MeCbl/AdoCbl synthesis), demonstrated by expression/complementation of cblD patient
      fibroblasts.
    action: ACCEPT
    reason: >-
      Core biological process, directly supported; duplicates the acts_upstream_of_or_within
      annotation from the same paper with an involved_in qualifier, both valid.
    supported_by:
    - reference_id: PMID:22156578
      supporting_text: supporting the role of cblD protein as a branch point in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27771510
  qualifier: enables
  review:
    summary: >-
      Protein binding annotation from co-IP/proximity-ligation demonstrating MMADHC
      interactions with methionine synthase (MTR/Q99707), methionine synthase reductase
      (MTRR/Q9UBK8) and MMACHC (Q9Y4U1) as part of a cytosolic multiprotein cobalamin-handling
      complex. These are biologically meaningful partners, but the term itself is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare "protein binding" does not convey function; the meaningful interactions
      (MMACHC/MTR/MTRR) reflect the cytosolic cobalamin-carrier complex and are captured by
      the molecular carrier activity MF and cobalamin metabolic process BP terms. Experimental
      IPI, so not removed, but marked over-annotated.
    supported_by:
    - reference_id: PMID:27771510
      supporting_text: >-
        processing of Cbl in cytoplasm occurs in a multiprotein complex composed of at least
        MS, MSR, MMACHC and MMADHC
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23415655
  qualifier: enables
  review:
    summary: >-
      Protein binding annotation for the MMADHC (CblD)-MMACHC (CblC, Q9Y4U1) interaction,
      shown biochemically to isolate a CblC-CblD complex that partitions cobalamin between
      the AdoCbl and MeCbl assimilation pathways.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The MMACHC interaction is central to MMADHC biology, but "protein binding" is
      uninformative; the functional consequence (adaptor/branch-point cobalamin carrier) is
      captured by molecular carrier activity and cobalamin metabolic process. Experimental
      IPI, not removed.
    supported_by:
    - reference_id: PMID:23415655
      supporting_text: an adapter function for CblD
    - reference_id: PMID:23415655
      supporting_text: functions downstream of CblC in the cofactor assimilation pathway
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23270877
  qualifier: located_in
  review:
    summary: >-
      Direct experimental cytoplasmic localization of MMADHC (immunofluorescence/subcellular
      fractionation), consistent with its cytosolic branch-point activity.
    action: ACCEPT
    reason: >-
      Correct but more general than the concurrently annotated cytosol (GO:0005829) term.
      Accept as valid localization.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:23270877
  qualifier: located_in
  review:
    summary: >-
      Direct experimental evidence that MMADHC has a mitochondrial pool in addition to its
      cytoplasmic pool, consistent with its role in routing cobalamin toward the
      mitochondrial AdoCbl branch and with its predicted mitochondrial transit peptide.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine mitochondrial localization, but the decisive branch-point/adaptor activity is
      cytosolic; retained as non-core.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IDA
  original_reference_id: PMID:24722857
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental involvement in cobalamin metabolism, from domain-mapping/rescue
      experiments showing that specific MMADHC regions differentially regulate AdoCbl and
      MeCbl synthesis (mapping to the three cblD phenotypes).
    action: ACCEPT
    reason: >-
      Core biological process, directly demonstrated by functional-domain characterization.
    supported_by:
    - reference_id: PMID:24722857
      supporting_text: specific regions of MMADHC are
    - reference_id: PMID:24722857
      supporting_text: must be converted into two coenzyme
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3318571
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation localizing MMADHC to the cytosol, consistent with the
      experimental cytosolic localization and its cytosolic branch-point function.
    action: ACCEPT
    reason: >-
      Concordant with the IDA cytosol annotation; retained as a core location.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149494
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation (MMACHC:cob(II)alamin binds MMADHC) localizing MMADHC to the
      cytosol, the compartment where it receives cobalamin from MMACHC.
    action: ACCEPT
    reason: >-
      Concordant with experimental cytosol localization; retained as a core location.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149563
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation localizing MMADHC to the cytosol, matching the experimental
      cytosolic localization and function.
    action: ACCEPT
    reason: >-
      Concordant with the IDA cytosol annotation; retained as a core location.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3204318
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS annotation (cob(II)alamin transferred from MMACHC:MMADHC:cob(II)alamin to
      MTRR:MTR) localizing MMADHC to the cytosol, consistent with its cytosolic
      cobalamin-handoff role within the MMACHC/MTR/MTRR complex.
    action: ACCEPT
    reason: >-
      Concordant with experimental cytosol localization; retained as a core location.
    supported_by:
    - reference_id: PMID:23270877
      supporting_text: MMADHC is both mitochondrial and cytoplasmic
    - reference_id: PMID:27771510
      supporting_text: >-
        processing of Cbl in cytoplasm occurs in a multiprotein complex composed of at least
        MS, MSR, MMACHC and MMADHC
core_functions:
- description: >-
    Cobalamin-trafficking branch-point/adaptor activity: acting downstream of MMACHC (cblC)
    in the cytosol, MMADHC receives the common cob(II)alamin intermediate and partitions it
    between the cytosolic methylcobalamin (MeCbl) branch supplying methionine synthase (MTR)
    and the mitochondrial adenosylcobalamin (AdoCbl) branch supplying methylmalonyl-CoA
    mutase (MMUT).
  molecular_function:
    id: GO:0140104
    label: molecular carrier activity
  directly_involved_in:
  - id: GO:0009235
    label: cobalamin metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:22156578
    supporting_text: supporting the role of cblD protein as a branch point in
  - reference_id: PMID:23415655
    supporting_text: an adapter function for CblD
  - reference_id: PMID:23270877
    supporting_text: MMADHC acts as a branch point for vitamin B(12) delivery to
proposed_new_terms: []
suggested_questions:
- question: >-
    What molecular signals determine the partitioning of MMADHC between its cytosolic and
    mitochondrial pools, and does mitochondrial import of MMADHC itself carry cobalamin?
- question: >-
    Is the Cys261-mediated interprotein Co-S coordination with MMACHC-bound cob(II)alamin the
    general mechanism of cobalamin handoff, or only one of several transfer modes?
suggested_experiments:
- description: >-
    Structure/cryo-EM of the full cytosolic MMACHC-MMADHC-MTR-MTRR complex with bound
    cobalamin to define the cofactor-handoff geometry and the basis of MeCbl-versus-AdoCbl
    branch selection.
- description: >-
    Quantitative flux measurements of MeCbl versus AdoCbl synthesis in cells expressing
    domain-swapped or transit-peptide-modified MMADHC variants to test how localization and
    domain boundaries set the branch point.
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: file:human/MMADHC/MMADHC-uniprot.txt
  title: UniProtKB entry Q9H3L0 (MMAD_HUMAN), Cobalamin trafficking protein CblD
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt record for MMADHC; supports cytoplasmic/mitochondrial localization, the
      MMACHC heterodimer, and the coenzyme-partitioning function.
- id: PMID:21071249
  title: Interaction between MMACHC and MMADHC, two human proteins participating in
    intracellular vitamin B₁₂ metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Confirms direct MMADHC-MMACHC interaction by SPR and bacterial two-hybrid; supports
      the carrier/adaptor role downstream of MMACHC.
- id: PMID:22156578
  title: Molecular mechanisms leading to three different phenotypes in the cblD defect
    of intracellular cobalamin metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes MMADHC as a branch point partitioning cytosolic MeCbl vs mitochondrial
      AdoCbl synthesis; mutation position correlates with the three cblD phenotypes.
- id: PMID:23270877
  title: Subcellular location of MMACHC and MMADHC, two human proteins central to
    intracellular vitamin B(12) metabolism.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct evidence (immunofluorescence/fractionation) that MMADHC is both cytosolic and
      mitochondrial and acts as a branch point downstream of MMACHC.
- id: PMID:23415655
  title: The C-terminal domain of CblD interacts with CblC and influences intracellular
    cobalamin partitioning.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Shows CblD functions downstream of CblC as an adapter controlling AdoCbl/MeCbl
      partitioning; C-terminal domain mediates the CblC interaction.
- id: PMID:24722857
  title: Characterization of functional domains of the cblD (MMADHC) gene product.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Domain-mapping/rescue experiments defining regions of MMADHC that differentially
      regulate AdoCbl vs MeCbl synthesis, matching the three cblD phenotypes.
- id: PMID:27771510
  title: Methionine synthase and methionine synthase reductase interact with MMACHC
    and with MMADHC.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Demonstrates a cytosolic multiprotein complex (MMACHC, MMADHC, MTR, MTRR) that
      shuttles cobalamin toward methionine synthase.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale HuRI binary-interactome map; source of the bare protein-binding IPIs
      (CREB5, POU4F2, TBC1D7, CINP) that are not established MMADHC functional partners.
- id: PMID:32871076
  title: An Interprotein Co-S Coordination Complex in the B(12)-Trafficking Pathway.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies Cys261 of CblD/MMADHC as a sulfur ligand to MMACHC-bound cob(II)alamin,
      defining a molecular cobalamin-handoff mechanism.
- 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-throughput mitochondrial proteome detecting MMADHC; corroborates the
      mitochondrial pool.
- id: Reactome:R-HSA-9759218
  title: Cobalamin (Cbl) metabolism
  findings: []
- id: Reactome:R-HSA-3149494
  title: MMACHC:cob(II)alamin binds MMADHC
  findings: []
- id: Reactome:R-HSA-3149563
  title: MMADHC targets transport of cytosolic cob(II)alamin to mitochondria
  findings: []
- id: Reactome:R-HSA-3204318
  title: cob(II)alamin is transferred from MMACHC:MMADHC:cob(II)alamin to MTRR:MTR
  findings: []
- id: Reactome:R-HSA-3318571
  title: Defective MMADHC does not bind MMACHC:B12r
  findings: []