MMADHC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic file:human/MMADHC/MMADHC-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:23270877}.
GO:0009235 cobalamin metabolic process	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:22156578 supporting the role of cblD protein as a branch point in PMID:23270877 MMADHC acts as a branch point for vitamin B(12) delivery to
GO:0140104 molecular carrier activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:23415655 an adapter function for CblD PMID:22156578 supporting the role of cblD protein as a branch point in
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (UniProt SubCell mapping) annotation to cytoplasm. Consistent with the documented cytoplasmic pool of MMADHC, where its branch-point/adaptor activity occurs. Reason: Correct but general; the more specific experimentally supported cytosol term (GO:0005829) is also annotated. Accept as a valid, if broad, localization. Supporting Evidence: file:human/MMADHC/MMADHC-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:23270877}.
GO:0005739 mitochondrion	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic (UniProt SubCell mapping) annotation to mitochondrion, matching the predicted N-terminal mitochondrial transit peptide and the experimentally observed mitochondrial pool. Reason: Mitochondrial localization is real and supported (transit peptide; IDA; HTP), but secondary to the cytosolic branch-point activity, so kept as non-core. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0009235 cobalamin metabolic process	IEA GO_REF:0000002	ACCEPT	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. Reason: Correct biological process, redundant with the well-supported IBA/IDA annotations to the same term. Represents a core process. Supporting Evidence: PMID:22156578 supporting the role of cblD protein as a branch point in
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:32296183 we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'.
GO:0009235 cobalamin metabolic process	TAS Reactome:R-HSA-9759218	ACCEPT	Summary: Reactome pathway annotation (Cobalamin metabolism) placing MMADHC in cobalamin metabolic process. Consistent with all other evidence for this gene. Reason: Traceable author statement from Reactome for a core biological process; concordant with the IBA/IDA/IEA annotations to the same term. Supporting Evidence: PMID:23270877 MMADHC acts as a branch point for vitamin B(12) delivery to
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	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. Reason: Confirms mitochondrial localization but this compartment is secondary to the cytosolic branch-point activity; kept as non-core localization. Supporting Evidence: PMID:34800366 high-confidence human mitochondrial proteome PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0140104 molecular carrier activity	TAS Reactome:R-HSA-3149563	ACCEPT	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. 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. Supporting Evidence: PMID:23415655 an adapter function for CblD
GO:0140104 molecular carrier activity	EXP PMID:21071249 Interaction between MMACHC and MMADHC, two human proteins pa...	ACCEPT	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. Reason: The MMACHC-MMADHC interaction underpins MMADHC's role as a downstream cobalamin carrier/adaptor; molecular carrier activity is the correct MF term. Supporting Evidence: PMID:21071249 MMADHC was confirmed as a binding
GO:0005829 cytosol	IDA PMID:23270877 Subcellular location of MMACHC and MMADHC, two human protein...	ACCEPT	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. 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. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0009235 cobalamin metabolic process	IDA PMID:22156578 Molecular mechanisms leading to three different phenotypes i...	ACCEPT	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. Reason: Core biological process, directly demonstrated. The acts_upstream_of_or_within qualifier reflects the regulatory branch-point role. Supporting Evidence: PMID:22156578 supporting the role of cblD protein as a branch point in PMID:22156578 correlate with the biochemical phenotype
GO:0140104 molecular carrier activity	IDA PMID:22156578 Molecular mechanisms leading to three different phenotypes i...	ACCEPT	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. Reason: Molecular carrier activity is the appropriate non-enzymatic MF term for this cofactor-partitioning adaptor; directly supported by the phenotype/rescue data. Supporting Evidence: PMID:22156578 supporting the role of cblD protein as a branch point in
GO:0140104 molecular carrier activity	IDA PMID:32871076 An Interprotein Co-S Coordination Complex in the B(12)-Traff...	ACCEPT	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. Reason: Biochemical/structural demonstration of direct cobalamin coordination by MMADHC in the trafficking pathway strongly supports molecular carrier activity as its MF. Supporting Evidence: PMID:32871076 CblD provides a sulfur ligand to cob(II)alamin bound to CblC PMID:32871076 Cys-261 on CblD as the sulfur donor
GO:0005829 cytosol	IDA PMID:23270877 Subcellular location of MMACHC and MMADHC, two human protein...	ACCEPT	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). 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. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0009235 cobalamin metabolic process	IDA PMID:22156578 Molecular mechanisms leading to three different phenotypes i...	ACCEPT	Summary: Direct experimental involvement in cobalamin metabolic process (branch-point control of MeCbl/AdoCbl synthesis), demonstrated by expression/complementation of cblD patient fibroblasts. 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. Supporting Evidence: PMID:22156578 supporting the role of cblD protein as a branch point in
GO:0005515 protein binding	IPI PMID:27771510 Methionine synthase and methionine synthase reductase intera...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:27771510 processing of Cbl in cytoplasm occurs in a multiprotein complex composed of at least MS, MSR, MMACHC and MMADHC
GO:0005515 protein binding	IPI PMID:23415655 The C-terminal domain of CblD interacts with CblC and influe...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:23415655 an adapter function for CblD PMID:23415655 functions downstream of CblC in the cofactor assimilation pathway
GO:0005737 cytoplasm	IDA PMID:23270877 Subcellular location of MMACHC and MMADHC, two human protein...	ACCEPT	Summary: Direct experimental cytoplasmic localization of MMADHC (immunofluorescence/subcellular fractionation), consistent with its cytosolic branch-point activity. Reason: Correct but more general than the concurrently annotated cytosol (GO:0005829) term. Accept as valid localization. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0005739 mitochondrion	IDA PMID:23270877 Subcellular location of MMACHC and MMADHC, two human protein...	KEEP AS NON CORE	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. Reason: Genuine mitochondrial localization, but the decisive branch-point/adaptor activity is cytosolic; retained as non-core. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0009235 cobalamin metabolic process	IDA PMID:24722857 Characterization of functional domains of the cblD (MMADHC) ...	ACCEPT	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). Reason: Core biological process, directly demonstrated by functional-domain characterization. Supporting Evidence: PMID:24722857 specific regions of MMADHC are PMID:24722857 must be converted into two coenzyme
GO:0005829 cytosol	TAS Reactome:R-HSA-3318571	ACCEPT	Summary: Reactome TAS annotation localizing MMADHC to the cytosol, consistent with the experimental cytosolic localization and its cytosolic branch-point function. Reason: Concordant with the IDA cytosol annotation; retained as a core location. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0005829 cytosol	TAS Reactome:R-HSA-3149494	ACCEPT	Summary: Reactome TAS annotation (MMACHC:cob(II)alamin binds MMADHC) localizing MMADHC to the cytosol, the compartment where it receives cobalamin from MMACHC. Reason: Concordant with experimental cytosol localization; retained as a core location. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0005829 cytosol	TAS Reactome:R-HSA-3149563	ACCEPT	Summary: Reactome TAS annotation localizing MMADHC to the cytosol, matching the experimental cytosolic localization and function. Reason: Concordant with the IDA cytosol annotation; retained as a core location. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic
GO:0005829 cytosol	TAS Reactome:R-HSA-3204318	ACCEPT	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. Reason: Concordant with experimental cytosol localization; retained as a core location. Supporting Evidence: PMID:23270877 MMADHC is both mitochondrial and cytoplasmic PMID:27771510 processing of Cbl in cytoplasm occurs in a multiprotein complex composed of at least MS, MSR, MMACHC and MMADHC

Gene Description

Existing Annotations Review

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References

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