MMACHC (CblC; "cyanocobalamin reductase / alkylcobalamin dealkylase") is the cytosolic vitamin B12 (cobalamin) processing chaperone-enzyme that performs the first intracellular tailoring step on incoming dietary/circulating cobalamin. It removes the upper axial (beta) ligand of cob(III)alamin to generate a common cob(II)alamin/cob(I)alamin intermediate that is then partitioned to the two downstream B12-dependent enzymes: methylcobalamin for cytosolic methionine synthase (MTR) and 5'-deoxyadenosylcobalamin for mitochondrial methylmalonyl-CoA mutase (MMUT). Using a divergent NADPH-dependent flavin reductase (nitroreductase-like) scaffold with FAD or FMN as prosthetic group, it catalyzes reductive decyanation of cyanocobalamin (the inactive dietary form) to cob(II)alamin plus cyanide (EC 1.16.1.6), and, via an arginine-rich glutathione-binding pocket, glutathione-dependent dealkylation of alkylcobalamins (methyl- and adenosylcobalamin) by nucleophilic displacement of the alkyl group to yield cob(I)alamin and an S-alkylglutathione (EC 2.5.1.151); cysteine and homocysteine cannot substitute for glutathione. Cobalamin is bound in the base-off configuration. MMACHC binds cobalamin and interacts with the CblD protein MMADHC (which partitions cofactor between the methyl- and adenosylcobalamin routes) and with the lysosomal B12 exporters LMBD1/LMBRD1 and ABCD4 that deliver cobalamin to it, and it participates in a cytosolic multiprotein processing complex with MMADHC, MTR and MTRR. Loss of MMACHC function causes cblC disease (combined methylmalonic aciduria and homocystinuria), the most common inborn error of intracellular cobalamin metabolism, because both the adenosylcobalamin and methylcobalamin arms are simultaneously deprived of their cofactor.
Definition: Catalysis of the reaction: an R-cob(III)alamin + glutathione = cob(I)alamin + an S-substituted glutathione + H(+). This is the EC 2.5.1.151 activity of MMACHC/CblC that dealkylates alkylcobalamins (methylcobalamin, adenosylcobalamin) using glutathione as the nucleophile.
Justification: GO currently has no molecular-function term specific to EC 2.5.1.151; MMACHC's dealkylase activity is mapped to the general parent GO:0016765 (transferase, transferring alkyl or aryl other than methyl) and, imprecisely, to demethylase activity. A dedicated term would allow accurate annotation of this well-characterized cobalamin-processing chemistry.
Parent term: transferase activity, transferring alkyl or aryl (other than methyl) groups
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Phylogenetic (PAN-GO) inference that MMACHC is active in the cytoplasm. MMACHC is a well-established cytosolic protein, so the localization is correct, but "cytoplasm" is a general parent of the more precise "cytosol" term that is directly supported experimentally. Reason: The cytoplasmic localization is correct but the more specific cytosol term (GO:0005829) is directly supported by immunofluorescence/fractionation and better represents where the enzyme acts. Proposed replacements: cytosol Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0009235 cobalamin metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that MMACHC is involved in cobalamin metabolism. This is the central, well-supported biological process for MMACHC: it processes incoming cobalamin into the common intermediate feeding both active cofactor pools. Reason: Correct and core. MMACHC catalyzes the first intracellular tailoring step of cobalamin, and IBA is consistent with the direct experimental evidence. Supporting Evidence: PMID:25809485 assimilation of dietary cobalamin into the active cofactor forms |
| GO:0032451 demethylase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic inference of demethylase activity, reflecting MMACHC's dealkylation of methylcobalamin. Mechanistically MMACHC removes the methyl group from cobalamin by glutathione-dependent nucleophilic S-alkyltransfer, not classic substrate demethylation; the essence (methyl removal) is right but the term flavor is imprecise. Reason: MMACHC's methylcobalamin activity is a glutathione S-alkyltransferase (EC 2.5.1.151) that transfers the methyl group to glutathione, better captured by the alkyl transferase term (GO:0016765) that GOA already applies. "Demethylase activity" (typically implying oxidative or hydrolytic demethylation of a substrate) mischaracterizes the chemistry. Proposed replacements: transferase activity, transferring alkyl or aryl (other than methyl) groups Supporting Evidence: PMID:19801555 using the thiolate of glutathione for nucleophilic PMID:21697092 the first example of an enzyme with glutathione transferase |
| GO:0033787 cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cyanocobalamin reductase (decyanase) activity. This is a core, directly demonstrated MMACHC molecular function: FAD/FMN + NADPH-dependent reductive decyanation of cyanocobalamin to cob(II)alamin. Reason: Correct and core; IBA agrees with strong experimental evidence (EXP/IDA) for the decyanation reaction. Supporting Evidence: PMID:18779575 the trafficking chaperone, MMACHC, catalyzes a PMID:19700356 wild-type MMACHC is able to reductively decyanate |
| GO:0071949 FAD binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of FAD binding. MMACHC is a divergent flavin reductase that uses FAD (or FMN) as a prosthetic group to catalyze reductive decyanation; FAD binding is directly demonstrated. Reason: Correct and core cofactor-binding function, supported experimentally and by structure. Supporting Evidence: PMID:21697092 can use FMN or FAD as a prosthetic group to catalyze reductive decyanation |
| GO:0031419 cobalamin binding | IDA PMID:19700356 Mechanism of vitamin B12-responsiveness in cblC methylmaloni... | NEW | Summary: Cobalamin binding is a core molecular function directly demonstrated for MMACHC: it binds cyanocobalamin (and hydroxocobalamin) with tight affinity in the base-off configuration, and pathogenic mutations (e.g. G147D) abolish cobalamin binding. Present in UniProt (GO:0031419, IEA:UniProtKB-KW) but not yet in the curated GOA set, so added here as NEW. Reason: MMACHC's substrate-binding function (cobalamin binding) underlies both its decyanase and dealkylase activities and is directly evidenced structurally and biochemically; it should be an explicit annotation. Supporting Evidence: PMID:19700356 MMACHC binds CNCbl in the base-off form PMID:22642810 The encoded MMACHC protein binds intracellular Cbl derivatives with |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation to cytosol from the UniProt subcellular-location mapping. Consistent with the experimentally determined cytosolic localization of MMACHC. Reason: Correct; matches direct experimental evidence for cytosolic localization. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0033787 cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of cyanocobalamin reductase activity via RHEA:16113/EC:1.16.1.6 mapping. This exactly matches the experimentally established decyanation reaction of MMACHC. Reason: Correct EC/RHEA-to-GO mapping for a directly demonstrated catalytic activity; core function. Supporting Evidence: PMID:25809485 catalyzes the elimination of the upper axial ligand in cobalamin |
| GO:0005515 protein binding | IPI PMID:23825108 Interaction between methionine synthase isoforms and MMACHC:... | MARK AS OVER ANNOTATED | Summary: IntAct IPI capturing the interaction of MMACHC with methionine synthase (MTR, Q99707), part of the cytosolic cobalamin-processing complex. The specific partner is biologically relevant but the bare "protein binding" term is uninformative. Reason: Per curation guidelines, "protein binding" (GO:0005515) is uninformative; the informative content (MMACHC-MTR interaction) is captured by the interaction data and the process/complex annotations. Retain the underlying IPI evidence but do not treat as a core molecular function. Supporting Evidence: PMID:23825108 interaction of MS with MMACHC may |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from a proteome-scale interactome study capturing an interaction with CCT6B (Q92526, a CCT/TRiC chaperonin subunit). High-throughput, uninformative bare protein-binding annotation. Reason: "Protein binding" is uninformative and this is a high-throughput proteome-scale contact with a chaperonin subunit, not an established functional partnership. Keep the evidence but not as a core function. Supporting Evidence: PMID:33961781 interactome |
| GO:0009235 cobalamin metabolic process | TAS Reactome:R-HSA-9759218 | ACCEPT | Summary: Reactome traceable-author annotation placing MMACHC in cobalamin metabolism. Concordant with the core biological role and with the IDA/IBA cobalamin-metabolic-process annotations. Reason: Correct and core; Reactome pathway curation agrees with experimental evidence. Supporting Evidence: PMID:25809485 assimilation of dietary cobalamin into the active cofactor forms |
| GO:0033787 cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity | TAS Reactome:R-HSA-3149519 | ACCEPT | Summary: Reactome TAS for the "MMACHC decyanates CNCbl" reaction, annotated to cyanocobalamin reductase activity. Matches the directly demonstrated decyanation function. Reason: Correct and core; consistent with EXP/IDA evidence for decyanation. Supporting Evidence: PMID:18779575 the trafficking chaperone, MMACHC, catalyzes a |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence IDA reporting a nucleoplasmic signal. MMACHC is a soluble cytosolic enzyme; dedicated localization studies place it in the cytoplasm/cytosol, not the nucleus. A nuclear pool is not part of its established biology. Reason: Not a core or well-supported localization. The high-throughput antibody signal conflicts with dedicated subcellular-localization work showing MMACHC is cytoplasmic; treat as an over-annotation rather than removing the underlying HPA observation. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0033787 cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity | EXP PMID:18779575 Decyanation of vitamin B12 by a trafficking chaperone. | ACCEPT | Summary: Direct experimental demonstration that MMACHC catalyzes reductive decyanation of cyanocobalamin, cleaving the Co-CN bond using NADPH-derived electrons to yield cob(II)alamin. This is the founding evidence for the decyanase activity. Reason: Core molecular function, directly demonstrated in the paper that first defined the reaction. Supporting Evidence: PMID:18779575 the trafficking chaperone, MMACHC, catalyzes a PMID:18779575 The product, cob(II)alamin, is a known substrate for assimilation into |
| GO:0033787 cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity | EXP PMID:21697092 Structural basis of multifunctionality in a vitamin B12-proc... | ACCEPT | Summary: Structural and biochemical characterization confirming MMACHC's reductive decyanation of cyanocobalamin, using FMN or FAD as prosthetic group on a divergent flavin-reductase scaffold. Reason: Core molecular function, directly demonstrated and structurally rationalized. Supporting Evidence: PMID:21697092 the reductive decyanation of PMID:21697092 can use FMN or FAD as a prosthetic group to catalyze reductive decyanation |
| GO:0033787 cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity | EXP PMID:25809485 Pathogenic mutations differentially affect the catalytic act... | ACCEPT | Summary: Mutational/kinetic study confirming decyanation activity of MMACHC (CblC) and showing it is largely preserved in R161Q/R161G mutants (which instead lose dealkylation), reinforcing the decyanase assignment. Reason: Core molecular function, directly demonstrated; decyanation is separable from dealkylation. Supporting Evidence: PMID:25809485 decreased dealkylation but not decyanation |
| GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups | EXP PMID:19801555 A human vitamin B12 trafficking protein uses glutathione tra... | ACCEPT | Summary: Direct demonstration that MMACHC dealkylates alkylcobalamins (methyl- and adenosylcobalamin) by using the thiolate of glutathione for nucleophilic displacement, generating cob(I)alamin and an S-alkylglutathione (EC 2.5.1.151). GOA maps this glutathione S-alkyltransferase chemistry to GO:0016765. Reason: Core molecular function (the alkylcobalamin dealkylase / GSH S-alkyltransferase activity), directly demonstrated. No dedicated GO term for EC 2.5.1.151 exists, so this alkyltransferase term is the best available representation. Supporting Evidence: PMID:19801555 using the thiolate of glutathione for nucleophilic PMID:19801555 cysteine and homocysteine, cannot |
| GO:0016765 transferase activity, transferring alkyl or aryl (other than methyl) groups | EXP PMID:21697092 Structural basis of multifunctionality in a vitamin B12-proc... | ACCEPT | Summary: Structural study confirming MMACHC's glutathione transferase (dealkylation) activity toward alkylcobalamins on a scaffold unrelated to the classical GST superfamily. Reason: Core molecular function, directly demonstrated and structurally characterized. Supporting Evidence: PMID:21697092 the dealkylation of alkylcobalamins PMID:21697092 the first example of an enzyme with glutathione transferase |
| GO:0005829 cytosol | IDA PMID:23270877 Subcellular location of MMACHC and MMADHC, two human protein... | ACCEPT | Summary: Direct experimental determination (immunofluorescence and subcellular fractionation) that MMACHC is cytosolic. This is the definitive localization annotation for the protein. Reason: Core cellular component; directly demonstrated cytosolic localization. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | IDA PMID:23270877 Subcellular location of MMACHC and MMADHC, two human protein... | ACCEPT | Summary: Direct evidence that MMACHC is active in the cytosol, where it performs cobalamin processing. Same study as the located_in cytosol annotation, with the active-in qualifier reflecting the site of catalysis. Reason: Core cellular component with appropriate is_active_in qualifier; cytosol is where MMACHC carries out cobalamin processing. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0016491 oxidoreductase activity | IDA PMID:21697092 Structural basis of multifunctionality in a vitamin B12-proc... | MODIFY | Summary: Oxidoreductase activity reflecting the reductive decyanation reaction of MMACHC. Correct but a general parent of the specific cyanocobalamin reductase term. Reason: The essence is correct (MMACHC is a reductase) but the term is too general; the specific cyanocobalamin reductase term (GO:0033787) is the informative representation of this activity. Proposed replacements: cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity Supporting Evidence: PMID:21697092 the reductive decyanation of |
| GO:0005515 protein binding | IPI PMID:27771510 Methionine synthase and methionine synthase reductase intera... | MARK AS OVER ANNOTATED | Summary: IPI capturing MMACHC interactions within the cytosolic cobalamin-processing complex (with MTR/Q99707, MMADHC/Q9H3L0, MTRR/Q9UBK8). Biologically important partners, but bare "protein binding" is uninformative. Reason: "Protein binding" (GO:0005515) conveys no functional specificity; the meaningful content (the MMACHC-MMADHC-MTR-MTRR processing complex) is better captured elsewhere. Retain the IPI evidence but not as a core molecular function. Supporting Evidence: PMID:27771510 at least MS, MSR, MMACHC and MMADHC |
| GO:0005515 protein binding | IPI PMID:25535791 Purification and interaction analyses of two human lysosomal... | MARK AS OVER ANNOTATED | Summary: IPI capturing MMACHC interactions with the lysosomal cobalamin exporters LMBD1/LMBRD1 (Q9NUN5) and ABCD4 (O14678), which deliver cobalamin to cytosolic MMACHC. Meaningful partners, but the bare protein-binding term is uninformative. Reason: "Protein binding" is uninformative; the biologically relevant LMBD1/ABCD4 interactions are captured by the interaction data. Keep the evidence, not as a core molecular function. Supporting Evidence: PMID:25535791 interacts with LMBD1 and ABCD4 with low nanomolar affinity |
| GO:0006749 glutathione metabolic process | IDA PMID:19801555 A human vitamin B12 trafficking protein uses glutathione tra... | KEEP AS NON CORE | Summary: IDA linking MMACHC to glutathione metabolism because its alkylcobalamin dealkylase reaction consumes glutathione (as nucleophile) to form S-alkylglutathione. This is a genuine but ancillary consequence of the core cobalamin-processing chemistry rather than a primary role in glutathione homeostasis. Reason: MMACHC uses glutathione as a co-substrate in dealkylation, so involvement in glutathione metabolism is defensible, but MMACHC's core role is cobalamin processing, not glutathione metabolism per se. Supporting Evidence: PMID:19801555 using the thiolate of glutathione for nucleophilic |
| GO:0006749 glutathione metabolic process | IDA PMID:22642810 Structure of MMACHC reveals an arginine-rich pocket and a do... | KEEP AS NON CORE | Summary: Structural IDA corroborating glutathione involvement: MMACHC has an arginine-rich pocket that binds GSH for dealkylation. As above, glutathione is a co-substrate of the core dealkylation reaction rather than the protein's primary metabolic role. Reason: Glutathione is consumed in the dealkylation reaction; annotation is defensible but ancillary to the core cobalamin-processing function. Supporting Evidence: PMID:22642810 arginine-rich pocket close to the Cbl |
| GO:0009235 cobalamin metabolic process | IDA PMID:19700356 Mechanism of vitamin B12-responsiveness in cblC methylmaloni... | ACCEPT | Summary: Direct experimental evidence placing MMACHC in cobalamin metabolism: wild-type MMACHC binds cyanocobalamin base-off and reductively decyanates it to cob(II)alamin, the precursor for the active cofactor forms. Reason: Core biological process, directly demonstrated. Supporting Evidence: PMID:19700356 wild-type MMACHC is able to reductively decyanate |
| GO:0009235 cobalamin metabolic process | IDA PMID:22642810 Structure of MMACHC reveals an arginine-rich pocket and a do... | ACCEPT | Summary: Direct evidence (structure + biochemistry) that MMACHC processes cobalamin derivatives, exhibiting FMN-dependent decyanase and GSH-dependent dealkylase activities central to cobalamin metabolism. Reason: Core biological process, directly demonstrated. Supporting Evidence: PMID:22642810 dealkylase activity toward alkyl-Cbls |
| GO:0016491 oxidoreductase activity | IDA PMID:19801555 A human vitamin B12 trafficking protein uses glutathione tra... | MODIFY | Summary: Oxidoreductase activity annotation reflecting MMACHC's reductive processing of cobalamin. Correct but a general parent of the specific cyanocobalamin reductase activity. Reason: Too general; the specific cyanocobalamin reductase term (GO:0033787) informatively captures MMACHC's reductase activity. Proposed replacements: cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity Supporting Evidence: PMID:19801555 transferase activity of MMACHC |
| GO:0032451 demethylase activity | IDA PMID:19801555 A human vitamin B12 trafficking protein uses glutathione tra... | MARK AS OVER ANNOTATED | Summary: IDA annotating demethylase activity based on MMACHC dealkylating methylcobalamin. The reaction is a glutathione-dependent S-alkyl (methyl) transfer to glutathione, not oxidative/hydrolytic substrate demethylation; the essence (methyl removal from cobalamin) is right but the term is the wrong chemistry. Reason: The chemistry is a glutathione S-alkyltransferase (EC 2.5.1.151), better represented by the alkyl transferase term (GO:0016765) that GOA already applies from the same paper. Treat demethylase activity as an imprecise over-annotation of the methylcobalamin dealkylation. Proposed replacements: transferase activity, transferring alkyl or aryl (other than methyl) groups Supporting Evidence: PMID:19801555 using the thiolate of glutathione for nucleophilic |
| GO:0033787 cyanocobalamin reductase (cyanide-eliminating) (NADP+) activity | IDA PMID:19700356 Mechanism of vitamin B12-responsiveness in cblC methylmaloni... | ACCEPT | Summary: Direct experimental evidence for cyanocobalamin reductase (decyanase) activity: wild-type MMACHC reductively decyanates CNCbl to cob(II)alamin given NADPH and FAD. Reason: Core molecular function, directly demonstrated. Supporting Evidence: PMID:19700356 wild-type MMACHC is able to reductively decyanate |
| GO:0042803 protein homodimerization activity | IPI PMID:22642810 Structure of MMACHC reveals an arginine-rich pocket and a do... | ACCEPT | Summary: MMACHC forms a domain-swapped homodimer (reciprocal exchange of a conserved PNRRP loop); dimerization is triggered by binding FMN or adenosylcobalamin and is required for proper dealkylation activity. Directly demonstrated by structure and solution studies. Reason: Substrate/cofactor-triggered homodimerization is a genuine, functionally relevant molecular property directly demonstrated for MMACHC. Supporting Evidence: PMID:22642810 dimerize to mediate the reciprocal |
| GO:0043295 glutathione binding | IDA PMID:22642810 Structure of MMACHC reveals an arginine-rich pocket and a do... | ACCEPT | Summary: MMACHC has an arginine-rich pocket adjacent to the cobalamin site that binds glutathione, required for the dealkylation reaction; mutation of the conserved arginines disrupts GSH binding and dealkylation. Directly demonstrated structurally. Reason: Glutathione binding is a genuine, mechanistically essential molecular function underpinning the alkylcobalamin dealkylase activity. Supporting Evidence: PMID:22642810 arginine-rich pocket close to the Cbl |
| GO:0070988 demethylation | IDA PMID:19801555 A human vitamin B12 trafficking protein uses glutathione tra... | MARK AS OVER ANNOTATED | Summary: Biological-process annotation of demethylation, again reflecting methylcobalamin dealkylation. As with GO:0032451, the underlying reaction is glutathione-dependent S-alkyl transfer, so the generic "demethylation" process term imprecisely characterizes the cobalamin-processing role. Reason: The process is more accurately the cobalamin metabolic/dealkylation process; generic demethylation over-annotates the methylcobalamin dealkylation step and is redundant with the cobalamin metabolic process annotations. Supporting Evidence: PMID:19801555 using the thiolate of glutathione for nucleophilic |
| GO:0071949 FAD binding | IDA PMID:19700356 Mechanism of vitamin B12-responsiveness in cblC methylmaloni... | ACCEPT | Summary: Direct evidence that MMACHC uses FAD (with NADPH) for reductive decyanation of cyanocobalamin. FAD binding is a core cofactor function of this flavin-reductase-family enzyme. Reason: Core cofactor-binding molecular function, directly demonstrated. Supporting Evidence: PMID:19700356 wild-type MMACHC is able to reductively decyanate |
| GO:0005515 protein binding | IPI PMID:23415655 The C-terminal domain of CblD interacts with CblC and influe... | MARK AS OVER ANNOTATED | Summary: IPI capturing the MMACHC (CblC) - MMADHC (CblD, Q9H3L0) interaction, an adapter partnership that partitions cobalamin cofactor between the AdoCbl and MeCbl routes. Biologically important but the bare protein-binding term is uninformative. Reason: "Protein binding" is uninformative; the meaningful MMACHC-MMADHC adapter interaction is captured by the interaction/complex information. Keep the IPI evidence, not as a core MF. Supporting Evidence: PMID:23415655 adapter function for CblD |
| GO:0005737 cytoplasm | IDA PMID:23270877 Subcellular location of MMACHC and MMADHC, two human protein... | MODIFY | Summary: Direct immunofluorescence/fractionation evidence that MMACHC is cytoplasmic. Correct, though the more precise cytosol term (also annotated from this same study) better represents the soluble localization. Reason: Correct localization but "cytoplasm" is a general parent; the specific cytosol term (GO:0005829) is directly supported and more informative. Proposed replacements: cytosol Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0009235 cobalamin metabolic process | IMP PMID:23825108 Interaction between methionine synthase isoforms and MMACHC:... | ACCEPT | Summary: IMP evidence: in cblC cells, MMACHC mutations disrupt formation of cob(II)alamin, and the MMACHC-methionine-synthase interaction is implicated in regulating cellular cobalamin processing, supporting MMACHC's role in cobalamin metabolism. Reason: Core biological process; loss/mutation of MMACHC impairs cobalamin processing, consistent with the direct catalytic evidence. Supporting Evidence: PMID:23825108 interaction of MS with MMACHC may |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3318576 | ACCEPT | Summary: Reactome TAS localizing MMACHC to the cytosol (in the "Defective MMACHC does not reduce Cbl" reaction context). Consistent with the experimentally established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3318590 | ACCEPT | Summary: Reactome TAS cytosol annotation (in the "Defective MMACHC does not decyanate CNCbl" reaction context). Consistent with the established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3095889 | ACCEPT | Summary: Reactome TAS cytosol annotation (MMACHC dealkylates RCbl reaction context). Consistent with the established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3149494 | ACCEPT | Summary: Reactome TAS cytosol annotation (MMACHC:cob(II)alamin binds MMADHC reaction context). Consistent with the established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3149519 | ACCEPT | Summary: Reactome TAS cytosol annotation (MMACHC decyanates CNCbl reaction context). Consistent with the established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3149563 | ACCEPT | Summary: Reactome TAS cytosol annotation (MMADHC targets transport of cytosolic cob(II)alamin to mitochondria reaction context). Consistent with the established cytosolic localization of MMACHC. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3204318 | ACCEPT | Summary: Reactome TAS cytosol annotation (cob(II)alamin transferred from MMACHC:MMADHC:cob(II)alamin to MTRR:MTR reaction context). Consistent with the established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3318571 | ACCEPT | Summary: Reactome TAS cytosol annotation (Defective MMADHC does not bind MMACHC:B12r reaction context). Consistent with the established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9759549 | ACCEPT | Summary: Reactome TAS cytosol annotation (Cob(I)alamin bound to MMACHC is oxidized to cob(II)alamin reaction context). Consistent with the established cytosolic localization. Reason: Correct cytosolic localization; consistent with the direct IDA cytosol evidence. Supporting Evidence: PMID:23270877 cytoplasmic while MMADHC is both mitochondrial and |
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Download this section (compressed HTML)Q: What are the physiological electron donor(s) and cytosolic flavoprotein oxidoreductase partner(s) that supply reducing equivalents to MMACHC for reductive decyanation in vivo?
Q: How is cobalamin handed off from MMACHC to MMADHC and the downstream MTR (methyl branch) versus the mitochondrial MMUT (adenosyl branch), and what governs the partitioning between the two arms?
Experiment: Structure/cryo-EM of the cytosolic MMACHC-MMADHC-MTR(-MTRR) processing complex with bound cobalamin to define the cofactor hand-off pathway and the structural basis of partitioning.
Experiment: Cell-based flux assays in MMACHC-null cells complemented with decyanation- versus dealkylation-selective mutants (e.g. R161Q) to dissect the relative in vivo contributions of the two catalytic activities to MeCbl and AdoCbl pools.
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