MMUT

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic (IBA) localization to cytoplasm. MMUT is a mitochondrial-matrix enzyme; cytoplasm is a broad, less-informative localization for this protein. Reason: MMUT is imported into the mitochondrial matrix after cleavage of its N-terminal transit peptide and its activity localizes to the mitochondria; cytoplasm captures at best a minor apoenzyme/import-intermediate pool and is far less precise than the mitochondrial-matrix annotation. The informative localization terms (mitochondrial matrix / mitochondrion) are retained. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH GRANULARITY MISMATCH Supporting Evidence: PMID:24458 All of the activity of these two enzymes was demonstrated to be in the mitochondria and those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:1902859 propionyl-CoA catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of MMUT to propionyl-CoA catabolism. This is the correct, non-obsolete biological-process term for MMUT's role, funneling propionate into the TCA cycle via succinyl-CoA. Reason: MMUT catalyzes the terminal step of propionyl-CoA catabolism (methylmalonyl-CoA to succinyl-CoA); this is its core physiological pathway. Note GO:0019678 "propionate metabolic process, methylmalonyl pathway" is now obsolete, so GO:1902859 is the appropriate BP term. Supporting Evidence: PMID:25125334 In humans, this reaction represents an important step in propionate catabolism, funneling metabolites from the breakdown of amino acids (valine, isoleucine, methionine, and threonine), odd‐chain fatty acids, and the side chain of cholesterol into the tricarboxylic acid cycle.
GO:0004494 methylmalonyl-CoA mutase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of the defining molecular function, methylmalonyl-CoA mutase activity. This is the core function of MMUT and is strongly supported experimentally. Reason: The IBA agrees with direct human enzyme assays and with the deeply conserved family assignment (EC 5.4.99.2). This is the central catalytic activity of the gene. Supporting Evidence: PMID:29056341 MUT is a mitochondrial matrix enzyme that uses coenzyme B12 or
GO:0031419 cobalamin binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of cobalamin binding. MMUT is an adenosylcobalamin-dependent enzyme; cobalamin (B12) binding is an essential cofactor function. Reason: MMUT requires adenosylcobalamin (AdoCbl) as its cofactor, coordinated in the C-terminal B12-binding domain; the cobalt is axially bound by His627. Cobalamin binding is a core, experimentally supported molecular function. Supporting Evidence: PMID:1978672 Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA).
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) mitochondrial localization. Consistent with all experimental and predictive evidence that MMUT is a mitochondrial enzyme. Reason: MMUT carries a cleavable mitochondrial transit peptide and is active in the mitochondrial matrix; the mitochondrion annotation is correct (matrix is the more precise term, annotated separately). Supporting Evidence: PMID:24458 All of the activity of these two enzymes was demonstrated to be in the mitochondria and those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0003824 catalytic activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic assignment of the generic parent term catalytic activity. True but uninformative relative to the specific methylmalonyl-CoA mutase activity annotation. Reason: MMUT is an enzyme, so catalytic activity is correct. It is a broad ancestor of the specific term GO:0004494; retaining it as a valid, non-misleading electronic rollup is acceptable, though it is not core. Supporting Evidence: PMID:25125334 catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA
GO:0004494 methylmalonyl-CoA mutase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment (multiple IEA methods, RHEA:22888 / EC 5.4.99.2) of the defining molecular function. Concordant with direct experimental evidence. Reason: The electronic mapping to methylmalonyl-CoA mutase activity is correct and corroborated by human enzyme assays; this is the core function. Supporting Evidence: PMID:25125334 Mitochondrial methylmalonyl‐CoA mutase (MUT, EC 5.4.99.2) catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA, requiring vitamin B12 (cobalamin) in the form of adenosylcobalamin (AdoCbl) as a cofactor.
GO:0005737 cytoplasm	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: UniProt subcellular-location keyword mapping to cytoplasm (SL-0086). MMUT is a mitochondrial-matrix enzyme; cytoplasm is imprecise. Reason: The cytoplasm keyword derives from the UniProt SUBCELLULAR LOCATION statement that lists Cytoplasm alongside Mitochondrion/matrix (from PMID:28943303), but the functional, activity-bearing localization is the mitochondrial matrix. Cytoplasm is a broad, less-informative term for MMUT. Supporting Evidence: PMID:24458 All of the activity of these two enzymes was demonstrated to be in the mitochondria and those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0005739 mitochondrion	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location keyword mapping to mitochondrion (SL-0173). Correct localization for MMUT. Reason: MMUT is a mitochondrial protein; the electronic localization is accurate. The mitochondrial matrix annotation is the more precise term. Supporting Evidence: PMID:24458 All of the activity of these two enzymes was demonstrated to be in the mitochondria
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location keyword mapping to mitochondrial matrix (SL-0170). This is the precise, correct localization of the active enzyme. Reason: Direct fractionation studies localize MMUT activity to the mitochondrial matrix (loosely bound to the inner membrane-matrix compartment); the electronic annotation matches the experimental evidence. Supporting Evidence: PMID:24458 those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0016853 isomerase activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic assignment of the parent term isomerase activity. True (MMUT is an intramolecular isomerase/mutase) but broad relative to GO:0004494. Reason: MMUT is EC 5.4.99.2, an isomerase; the term is a correct ancestor of the specific methylmalonyl-CoA mutase activity term. Valid non-core electronic rollup. Supporting Evidence: PMID:25125334 catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA
GO:0016866 intramolecular transferase activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic assignment of intramolecular transferase activity (mutase). Correct intermediate parent of methylmalonyl-CoA mutase activity. Reason: Methylmalonyl-CoA mutase is a carbon-skeleton mutase (intramolecular transfer of the thioester/carboxyl-bearing group), so GO:0016866 is an accurate ancestor of the specific term. Valid non-core electronic rollup. Supporting Evidence: PMID:25125334 catalyzes the reversible isomerisation of l‐methylmalonyl‐CoA to succinyl‐CoA
GO:0031419 cobalamin binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic assignment of cobalamin binding, based on the B12-binding domain signatures. Concordant with the experimental cofactor requirement. Reason: MMUT contains a cobalamin-binding domain and requires adenosylcobalamin; the electronic annotation matches the direct experimental evidence for cofactor binding. Supporting Evidence: PMID:1978672 Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme
GO:0046872 metal ion binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic assignment of metal ion binding, reflecting the cobalt ion of the bound adenosylcobalamin cofactor. Reason: The cofactor adenosylcobalamin contains a cobalt ion that is axially coordinated by His627 of MMUT, so metal (cobalt) ion binding is correct, if broad. It is captured more informatively by cobalamin binding. Supporting Evidence: PMID:20876572 vitamin B12-dependent methylmalonyl-CoA mutase
GO:0005515 protein binding	IPI PMID:20876572 Structures of the human GTPase MMAA and vitamin B12-dependen...	MARK AS OVER ANNOTATED	Summary: IntAct IPI (partner MMAA, Q8IVH4). Bare protein binding is uninformative as a molecular function; the biologically meaningful apo-MUT:MMAA interaction is captured by the homodimerization and positive-regulation-of-GTPase annotations. Reason: Per curation guidance, generic protein binding does not convey a specific molecular function and should not be treated as a core annotation. The underlying MMAA interaction is real and is documented; it is represented more usefully elsewhere. Supporting Evidence: PMID:20876572 the two proteins interact in vitro and in vivo
GO:0005515 protein binding	IPI PMID:28497574 Protein destabilization and loss of protein-protein interact...	MARK AS OVER ANNOTATED	Summary: IntAct IPI (partner MMAA, Q8IVH4) from the cblA-type MMA study. Bare protein binding is uninformative. Reason: Generic protein binding is not an informative molecular function. The MUT-MMAA interaction it reflects is documented, but is better represented by the positive-regulation-of-GTPase-activity annotation. Supporting Evidence: PMID:28497574 which is stimulated by an interaction with MUT
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IntAct IPI (partner HTT/huntingtin, P42858) from a neurodegenerative-disease interactome map. Bare protein binding is uninformative and this is a large-scale network interaction of uncertain physiological relevance to MMUT function. Reason: Generic protein binding conveys no specific molecular function. This is a high-throughput interactome/aggregation screen; the interaction does not inform MMUT's characterized enzymatic role. Supporting Evidence: PMID:32814053 Interactome maps are valuable resources to elucidate protein function and disease mechanisms.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IntAct IPI (partner CRYZ, Q08257) from a proteome-scale interactome study. Bare protein binding is uninformative. Reason: Generic protein binding is not an informative molecular function. This is a large-scale affinity-purification network dataset; the interaction does not inform MMUT's core function. Supporting Evidence: PMID:33961781 These networks model the interactome
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IntAct IPI (partner CRYZ, Q08257) from a multimodal cell-map study. Bare protein binding is uninformative. Reason: Generic protein binding conveys no specific molecular function. This is a large-scale mapping dataset; the interaction does not inform MMUT's core function. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics.
GO:0042802 identical protein binding	IPI PMID:20876572 Structures of the human GTPase MMAA and vitamin B12-dependen...	KEEP AS NON CORE	Summary: IntAct IPI (self, P22033), reflecting the MMUT homodimer. Real but represented more informatively by protein homodimerization activity. Reason: MMUT is a homodimer, so self-association is genuine, but identical protein binding is a weaker restatement of the homodimerization annotation; keep as non-core. Supporting Evidence: PMID:20876572 crystallized human MMAA in the GDP-bound form and human MUT in the apo, holo, and substrate-bound ternary forms
GO:1901290 succinyl-CoA biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of succinyl-CoA biosynthetic process. This is an accurate product-oriented description of the MMUT reaction (MM-CoA to succinyl-CoA). Reason: MMUT produces succinyl-CoA from methylmalonyl-CoA; the term correctly describes the product-forming aspect of its reaction. Complementary to the propionyl-CoA catabolic process annotation. Supporting Evidence: PMID:29056341 It catalyzes the conversion of methylmalonyl-CoA into succinyl-CoA, which allows recycling of branched carbon chains from amino acids and lipids into the tricarboxylic acid cycle (TCA cycle).
GO:0004494 methylmalonyl-CoA mutase activity	EXP PMID:1346616 Cloning and expression of a mutant methylmalonyl coenzyme A ...	ACCEPT	Summary: Experimental (EXP) demonstration of methylmalonyl-CoA mutase activity via cloning and expression of human MCM and characterization of a cobalamin-affinity mutant. Core function. Reason: This study expressed human MCM and characterized its catalytic behavior (including the G717V mut- mutant with ~1000-fold elevated Km for adenosylcobalamin), directly supporting methylmalonyl-CoA mutase activity as the gene's function. Supporting Evidence: PMID:1346616 an apparent Km (adenosylcobalamin) 1,000-fold higher than normal
GO:0004494 methylmalonyl-CoA mutase activity	EXP PMID:25125334 Functional characterization and categorization of missense m...	ACCEPT	Summary: Experimental (EXP) characterization of MUT activity across 23 recombinant patient missense variants, measuring succinate production from methylmalonyl-CoA. Core function. Reason: Wild-type and mutant MUT were assayed for conversion of [14C]methylmalonyl-CoA to [14C]succinate, directly measuring methylmalonyl-CoA mutase activity and its cofactor/substrate kinetics. Supporting Evidence: PMID:25125334 MUT activity was assayed in crude cell lysates by measuring the production of [14C]succinate from [14C]methylmalonyl‐CoA
GO:0004494 methylmalonyl-CoA mutase activity	EXP PMID:29056341 The Human Knockout Gene CLYBL Connects Itaconate to Vitamin ...	ACCEPT	Summary: Experimental (EXP) work using recombinant human MUT reconstituted with coenzyme B12; establishes methylmalonyl-CoA mutase activity and its inhibition by itaconyl-CoA. Core function. Reason: The study characterized recombinant human MUT enzymology (conversion of methylmalonyl-CoA to succinyl-CoA using coenzyme B12) and identified itaconyl-CoA as a cofactor-inactivating inhibitor, directly supporting the mutase activity. Supporting Evidence: PMID:29056341 itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B12-dependent methylmalonyl-CoA mutase (MUT)
GO:1901290 succinyl-CoA biosynthetic process	IDA PMID:1978672 Primary structure and activity of mouse methylmalonyl-CoA mu...	ACCEPT	Summary: Direct assay (IDA) of mutase activity producing succinyl-CoA from methylmalonyl-CoA. Accurate product-oriented description of the MMUT reaction. Reason: Enzyme assays of MCM demonstrated isomerization between methylmalonyl-CoA and succinyl-CoA, supporting involvement in succinyl-CoA biosynthesis. Supporting Evidence: PMID:1978672 an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA)
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput (HTP) mitochondrial proteome study placing MMUT among the high-confidence mitochondrial proteins (MitoCoP). Consistent with all other evidence. Reason: MMUT was classified in the >1,100-protein high-confidence human mitochondrial proteome, corroborating its mitochondrial localization. Supporting Evidence: PMID:34800366 defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-3322971	ACCEPT	Summary: Reactome traceable assertion (TAS) placing MMUT in the mitochondrial matrix (in the context of defective MUT failing to isomerise L-MM-CoA to succinyl-CoA). Correct localization. Reason: Reactome curates MMUT as a mitochondrial matrix enzyme; consistent with direct fractionation evidence. Supporting Evidence: PMID:24458 those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0004494 methylmalonyl-CoA mutase activity	IDA PMID:1978672 Primary structure and activity of mouse methylmalonyl-CoA mu...	ACCEPT	Summary: Direct assay (IDA) of methylmalonyl-CoA mutase activity for the cloned enzyme, with reaction kinetics similar to the human enzyme. Core function. Reason: The enzyme was directly assayed and shown to isomerize methylmalonyl-CoA to succinyl-CoA in an adenosylcobalamin-dependent manner, defining the core molecular function. Supporting Evidence: PMID:1978672 catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA)
GO:0004494 methylmalonyl-CoA mutase activity	IDA PMID:21138732 Protection and reactivation of human methylmalonyl-CoA mutas...	ACCEPT	Summary: Direct assay (IDA) of purified recombinant human MCM catalytic activity (and its protection/reactivation by MMAA). Core function. Reason: Purified recombinant MCM was assayed for its methylmalonyl-CoA mutase reaction kinetics, directly establishing the activity. Supporting Evidence: PMID:21138732 we examined the influence of human MMAA protein on the kinetics of the reaction catalyzed by methylmalonyl-CoA mutase (MCM) by testing both purified recombinant proteins in vitro
GO:0004494 methylmalonyl-CoA mutase activity	IDA PMID:24458 Intracellular localization of hepatic propionyl-CoA carboxyl...	ACCEPT	Summary: Direct assay (IDA) of methylmalonyl-CoA mutase activity in hepatic mitochondrial fractions (a rapid mutase assay was described). Core function. Reason: Methylmalonyl-CoA mutase activity was measured in mitochondrial fractions of human and rat liver, directly supporting the molecular function and its mitochondrial localization. Supporting Evidence: PMID:24458 a rapid enzymatic assay for methylmalonyl-CoA mutase was described.
GO:0004494 methylmalonyl-CoA mutase activity	IDA PMID:2453061 Molecular cloning of L-methylmalonyl-CoA mutase: gene transf...	ACCEPT	Summary: Direct assay (IDA) of MCM activity constituted by gene transfer of the cloned human MCM cDNA into COS cells. Core function. Reason: Cells transformed with the human MCM cDNA expressed increased methylmalonyl-CoA mutase enzymatic activity, directly demonstrating the function of the cloned gene. Supporting Evidence: PMID:2453061 Cells transformed with this clone expressed increased levels of MCM enzymatic activity.
GO:0004494 methylmalonyl-CoA mutase activity	IDA PMID:28943303 Human MMAA induces the release of inactive cofactor and rest...	ACCEPT	Summary: Direct assay (IDA) of recombinant human MCM activity, including altered kinetics in the presence of MMAA/GTP. Core function. Reason: Recombinant hMCM was assayed for its mutase reaction and cofactor kinetics (Km/Vmax for methylmalonyl-CoA), directly establishing methylmalonyl-CoA mutase activity. Supporting Evidence: PMID:28943303 Human mitochondrial methylmalonyl-CoA mutase (hMCM) is an isomerase that converts methylmalonyl-CoA to succinyl-CoA
GO:0005515 protein binding	IPI PMID:21138732 Protection and reactivation of human methylmalonyl-CoA mutas...	MARK AS OVER ANNOTATED	Summary: IPI (partner MMAA, Q8IVH4). MUT-MMAA interaction confirmed by yeast two-hybrid. Bare protein binding is uninformative as an MF. Reason: Generic protein binding is not an informative molecular function. The real MUT-MMAA interaction is documented and is better represented by the positive-regulation-of-GTPase-activity annotation. Supporting Evidence: PMID:21138732 Interaction between MCM and MMAA observed in vitro was confirmed in vivo by yeast two-hybrid system.
GO:0005515 protein binding	IPI PMID:28943303 Human MMAA induces the release of inactive cofactor and rest...	MARK AS OVER ANNOTATED	Summary: IPI (partner MMAA, Q8IVH4). Bare protein binding is uninformative as an MF; the MUT-MMAA complex is the biologically meaningful interaction. Reason: Generic protein binding conveys no specific molecular function. The MUT-MMAA complex formation demonstrated here is better captured by the regulatory and localization annotations. Supporting Evidence: PMID:28943303 restores methylmalonyl-CoA mutase activity through their complex formation
GO:0005737 cytoplasm	IDA PMID:28943303 Human MMAA induces the release of inactive cofactor and rest...	MARK AS OVER ANNOTATED	Summary: Direct-assay (IDA) localization including a cytoplasmic signal in human fibroblasts. MMUT is a mitochondrial-matrix enzyme; cytoplasm is imprecise/over-broad. Reason: This study reported the in vivo localization and colocalization of hMMAA with hMCM in fibroblast mitochondria; the functional pool of MMUT is mitochondrial-matrix. Cytoplasm at best reflects a minor apoenzyme/import-intermediate signal and is a less informative localization than the mitochondrial matrix annotation. Supporting Evidence: PMID:28943303 the in vivo localization of hMMAA and its colocalization with hMCM in human fibroblasts mitochondria were demonstrated.
GO:0005739 mitochondrion	IDA PMID:28943303 Human MMAA induces the release of inactive cofactor and rest...	ACCEPT	Summary: Direct-assay (IDA) mitochondrial localization of hMCM in human fibroblasts. Correct localization. Reason: Immunolocalization showed hMCM in fibroblast mitochondria (colocalizing with hMMAA), directly supporting the mitochondrial annotation. Supporting Evidence: PMID:28943303 the in vivo localization of hMMAA and its colocalization with hMCM in human fibroblasts mitochondria were demonstrated.
GO:0005759 mitochondrial matrix	IDA PMID:24458 Intracellular localization of hepatic propionyl-CoA carboxyl...	ACCEPT	Summary: Direct-assay (IDA) localization of MMUT activity to the mitochondrial inner-membrane/matrix compartment by subcellular fractionation. Precise, core localization. Reason: All MMUT activity fractionated with mitochondria and was loosely bound to the inner membrane-matrix portion, directly establishing the mitochondrial-matrix localization. Supporting Evidence: PMID:24458 those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0031419 cobalamin binding	IDA PMID:1978672 Primary structure and activity of mouse methylmalonyl-CoA mu...	ACCEPT	Summary: Direct assay (IDA) establishing adenosylcobalamin dependence/binding (cofactor requirement, Km for adenosylcobalamin). Core cofactor function. Reason: The enzyme is adenosylcobalamin-dependent with a defined Km for the cofactor, directly supporting cobalamin binding. Supporting Evidence: PMID:1978672 Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme
GO:0031419 cobalamin binding	IDA PMID:21138732 Protection and reactivation of human methylmalonyl-CoA mutas...	ACCEPT	Summary: Direct assay (IDA) of the cobalamin cofactor role, including cofactor oxidation during catalysis and its exchange by MMAA. Core cofactor function. Reason: The study addressed inactivation due to oxidation of the bound cobalamin and its reactivation by cofactor exchange, directly supporting cobalamin binding by MCM. Supporting Evidence: PMID:21138732 some adenosylcobalamin-dependent enzymes suffer inactivation during catalysis due to the oxidation of cobalamin
GO:0031419 cobalamin binding	IDA PMID:28943303 Human MMAA induces the release of inactive cofactor and rest...	ACCEPT	Summary: Direct assay (IDA) of the AdoCbl cofactor role, including OH2Cbl formation and removal/replacement of damaged cofactor. Core cofactor function. Reason: hMCM uses adenosylcobalamin (AdoCbl) and its oxidized inactive form (OH2Cbl) is removed via MMAA, directly supporting cobalamin binding. Supporting Evidence: PMID:28943303 employs highly reactive radicals from its cofactor (adenosylcobalamin, AdoCbl)
GO:0003924 GTPase activity	IDA PMID:20876572 Structures of the human GTPase MMAA and vitamin B12-dependen...	UNDECIDED	Summary: IDA annotation of GTPase activity to MMUT. In this paper the demonstrated GTPase is MMAA (the partner protein), whose GTPase activity is modulated by MUT; MUT itself is a B12 mutase with no GTPase domain. Reason: The abstract explicitly attributes GTPase activity to MMAA ("MMAA exhibits GTPase activity that is modulated by MUT"), and MMUT has no P-loop/GTPase fold, so assigning GTPase activity to MMUT appears to be a mis-attribution of the partner's activity. However, per curation policy I cannot read the full text to confirm exactly what was assayed for MMUT, so I flag this rather than removing an experimental annotation; if the assignment cannot be substantiated it should be removed. Supporting Evidence: PMID:20876572 MMAA exhibits GTPase activity that is modulated by MUT
GO:0031419 cobalamin binding	IDA PMID:20876572 Structures of the human GTPase MMAA and vitamin B12-dependen...	ACCEPT	Summary: Direct assay/structure (IDA) with adenosylcobalamin bound to MUT (holo and ternary crystal structures), supporting cobalamin binding. Core cofactor function. Reason: The crystal structures of human MUT were solved in apo, holo, and substrate-bound (ternary) forms with adenosylcobalamin, directly demonstrating cobalamin binding (the cobalt is axially coordinated by His627). Supporting Evidence: PMID:20876572 human MUT in the apo, holo, and substrate-bound ternary forms
GO:0042802 identical protein binding	IDA PMID:20876572 Structures of the human GTPase MMAA and vitamin B12-dependen...	KEEP AS NON CORE	Summary: IDA of self-association (MMUT homodimer) from crystallographic subunit analysis. Real but a weaker restatement of homodimerization activity. Reason: MMUT is a homodimer, so identical protein binding is genuine; it duplicates the more informative protein homodimerization activity annotation and is not a core function. Supporting Evidence: PMID:20876572 they show substantially different dimeric assembly and interaction
GO:0042803 protein homodimerization activity	IDA PMID:20876572 Structures of the human GTPase MMAA and vitamin B12-dependen...	KEEP AS NON CORE	Summary: IDA of homodimerization from the human MUT crystal structure. MMUT is an active homodimer; a genuine, structurally supported property. Reason: The human MUT crystal structures establish a homodimeric assembly. This is a real structural property enabling function, but it is ancillary to the core catalytic annotation. Supporting Evidence: PMID:20876572 they show substantially different dimeric assembly and interaction, compared with their bacterial counterparts
GO:0043547 positive regulation of GTPase activity	IDA PMID:20876572 Structures of the human GTPase MMAA and vitamin B12-dependen...	KEEP AS NON CORE	Summary: IDA that MUT modulates (stimulates) the GTPase activity of its partner MMAA. A genuine regulatory role, but ancillary to MMUT's core catalytic function. Reason: The apo-MUT:MMAA interaction modulates MMAA's GTPase activity; this GAP-like regulatory role is documented but is peripheral to MMUT's core mutase function. Supporting Evidence: PMID:20876572 MMAA exhibits GTPase activity that is modulated by MUT
GO:0043547 positive regulation of GTPase activity	IDA PMID:28497574 Protein destabilization and loss of protein-protein interact...	KEEP AS NON CORE	Summary: IDA that MUT stimulates MMAA GTPase activity; loss of this stimulation underlies cblA-type MMA. Genuine regulatory role, ancillary to core function. Reason: MMAA's GTPase activity is stimulated by interaction with MUT, and disease mutations reduce this stimulation; the regulatory role is supported but is not MMUT's core function. Supporting Evidence: PMID:28497574 This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT.
GO:0004494 methylmalonyl-CoA mutase activity	IMP PMID:28101778 Eight novel MUT loss-of-function missense mutations in Chine...	ACCEPT	Summary: IMP evidence from patient loss-of-function missense mutations that reduce MCM enzymatic activity in a functional assay. Supports the core mutase function. Reason: Eight novel MUT missense mutations reduced MCM protein and activity in a permissive assay, genetically implicating MMUT in methylmalonyl-CoA mutase activity. Supporting Evidence: PMID:28101778 the MCM activity of the mutations was reduced in a permissive assay.
GO:0004494 methylmalonyl-CoA mutase activity	IMP PMID:27167370 Molecular Genetic Characterization of 151 Mut-Type Methylmal...	ACCEPT	Summary: IMP evidence from a large mut-type MMA patient cohort (110 mutations) showing reduced MUT protein/activity. Supports the core mutase function. Reason: Molecular-genetic characterization of 151 mut-type MMA patients links MUT mutations to loss of MUT function (reduced protein and propionate incorporation), supporting methylmalonyl-CoA mutase activity as the gene's function. Supporting Evidence: PMID:27167370 Western blot analysis revealed reduced MUT protein for all 34 cell lines (27 mut(0) , seven mut(-) ) tested, suggesting protein instability as a major mechanism of deficiency in mut-type MMA.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-3159259	ACCEPT	Summary: Reactome TAS placing MMUT in the mitochondrial matrix (MMAA:MUT binds AdoCbl reaction). Correct localization. Reason: Reactome curates MMUT (and the MMAA:MUT complex) in the mitochondrial matrix, consistent with the experimental localization. Supporting Evidence: PMID:24458 those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-3322135	ACCEPT	Summary: Reactome TAS placing MMUT in the mitochondrial matrix (Defective MMAA does not protect MUT reaction). Correct localization. Reason: Reactome consistently curates MMUT in the mitochondrial matrix; consistent with the experimental fractionation evidence. Supporting Evidence: PMID:24458 those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-71010	ACCEPT	Summary: Reactome TAS placing MMUT in the mitochondrial matrix (MUT isomerises L-MM-CoA to SUCC-CoA reaction). Correct localization for the catalytic step. Reason: Reactome curates the MUT-catalyzed isomerization of L-methylmalonyl-CoA to succinyl-CoA in the mitochondrial matrix, matching the experimental localization. Supporting Evidence: PMID:24458 those enzymes were shown to be loosely bound to the inner membrane-matrix portion of the mitochondria.
GO:0050667 homocysteine metabolic process	IDA PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma...	MARK AS OVER ANNOTATED	Summary: Annotation derived from a GWAS association of a MUT-locus SNP with plasma homocysteine. The paper itself states MUT's catalytic activity is "hardly related to homocysteine"; any link is indirect (shared B12 dependence), not a direct molecular role of MMUT in homocysteine metabolism. Reason: The association is epidemiological/genetic and, per the authors, only indirectly related to MMUT function (via competition for vitamin B12 between mitochondrial MUT and cytosolic methionine synthase). MMUT does not act on homocysteine or its metabolites, so involvement in homocysteine metabolic process is an over-annotation. Supporting Evidence: PMID:20031578 While its catalytic activity is hardly related to homocysteine, MUT has frequently been associated with homocysteine metabolism because it is one of three vitamin B 12 dependant enzymes
GO:0072341 modified amino acid binding	IDA PMID:20031578 Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma...	MARK AS OVER ANNOTATED	Summary: Annotation from the same homocysteine GWAS paper. There is no biochemical demonstration that MMUT binds a modified amino acid; its characterized ligands are methylmalonyl-CoA and adenosylcobalamin. Reason: The GWAS study did not assay MMUT binding to any modified amino acid; MMUT's substrate is a CoA thioester and its cofactor is a corrinoid, not a modified amino acid. This molecular-function annotation does not fit the characterized biochemistry. Supporting Evidence: PMID:20031578 MUT encodes for the mitochondrial enzyme methylmalonyl-Coa mutase and as such, catalyses the isomeration of methylmalonyl-Coa into succinyl-Coa.
GO:0005739 mitochondrion	TAS PMID:2567699 Cloning of full-length methylmalonyl-CoA mutase from a cDNA ...	ACCEPT	Summary: Traceable assertion (TAS) of mitochondrial localization; the full-length cDNA cloning identified the N-terminal mitochondrial transit peptide. Correct localization. Reason: The cloning of full-length human MCM defined its mitochondrial-targeting N-terminus (the transit peptide, residues 1-32), supporting mitochondrial localization. Supporting Evidence: PMID:2567699 Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction.

Gene Description

Existing Annotations Review

Core Functions

Adenosylcobalamin (coenzyme B12)-dependent methylmalonyl-CoA mutase that catalyzes the reversible isomerization of (R)-methylmalonyl-CoA (L-methylmalonyl-CoA) to succinyl-CoA, the terminal step of propionyl-CoA catabolism, in the mitochondrial matrix.

Binds adenosylcobalamin (vitamin B12) as an essential catalytic cofactor; the cobalt of the corrinoid is axially coordinated by a conserved histidine in the C-terminal cobalamin-binding domain, and homolysis of the cobalt-carbon bond generates the radical intermediates required for isomerization.

References

📚 Additional Documentation

Notes

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