Affinage

MMACHC

Cyanocobalamin reductase / alkylcobalamin dealkylase · UniProt Q9Y4U1

Length
282 aa
Mass
31.7 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MMACHC is a cytoplasmic cobalamin (vitamin B12) processing enzyme that catalyzes removal of the upper axial ligand from all dietary cobalamin derivatives, serving as the essential first step in intracellular generation of the cofactors adenosylcobalamin and methylcobalamin (PMID:16311595, PMID:19447654). It adopts a nitroreductase fold that binds cobalamin in a base-off configuration as a domain-swapped dimer, performing FMN/NADPH-dependent reductive decyanation of cyanocobalamin and GSH-dependent dealkylation of alkylcobalamins through an arginine-rich active site that coordinates glutathione (PMID:22642810, PMID:19700356). MMACHC operates within a cytoplasmic multiprotein complex with MMADHC, methionine synthase, and methionine synthase reductase, where MMADHC acts downstream to partition processed cob(II)alamin between cytoplasmic and mitochondrial cofactor synthesis pathways (PMID:27771510, PMID:23415655). Biallelic loss-of-function mutations in MMACHC cause cblC-type combined methylmalonic aciduria and homocystinuria, with disease-associated mutations at Arg161 selectively impairing dealkylation and GSH binding while unmasking a futile thiol oxidase activity that promotes oxidative stress (PMID:16311595, PMID:25809485, PMID:28442570).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 High

    Identification of MMACHC as the cblC disease gene resolved a decades-long search for the genetic basis of the most common inborn error of intracellular cobalamin metabolism, establishing that this single gene is required for synthesis of both adenosylcobalamin and methylcobalamin.

    Evidence Homozygosity mapping and mutation identification in 204 patients, with retroviral complementation of cblC fibroblasts

    PMID:16311595

    Open questions at the time
    • Enzymatic mechanism unknown at this stage
    • Subcellular localization not determined
    • Protein partners not identified
  2. 2009 High

    Demonstration that MMACHC catalyzes both decyanation of cyanocobalamin (NADPH/FAD-dependent) and dealkylation of naturally occurring alkylcobalamins, with base-off CNCbl binding, defined the dual enzymatic activities and cofactor requirements of the protein.

    Evidence Radioisotopic substrate conversion in patient vs. control fibroblasts, in vitro enzymatic and binding assays with recombinant protein and cobalamin ligands

    PMID:19447654 PMID:19700356

    Open questions at the time
    • Three-dimensional structure not yet available
    • Mechanism of GSH involvement in dealkylation unknown
    • Protein interaction network not characterized
  3. 2010 High

    Biophysical characterization revealed that apo-MMACHC is thermolabile and stabilized by cobalamin binding, while identification of MMADHC as a direct physical partner established the first component of a cobalamin processing relay.

    Evidence Differential scanning fluorimetry of wild-type and R161Q proteins with cobalamin ligands; surface plasmon resonance and bacterial two-hybrid for MMACHC–MMADHC interaction

    PMID:20219402 PMID:21071249

    Open questions at the time
    • Structural basis of MMACHC–MMADHC interaction unknown
    • Whether MMACHC functions as monomer or oligomer unclear
    • Interaction with methionine synthase not yet tested
  4. 2012 High

    The crystal structure of MMACHC bound to AdoCbl revealed a nitroreductase scaffold with a domain-swapped dimer architecture and an arginine-rich GSH-binding pocket, providing the structural basis for dealkylation catalysis and explaining why Arg161 mutations cause disease; concurrent localization studies confirmed exclusive cytoplasmic residence.

    Evidence X-ray crystallography with site-directed mutagenesis and dealkylation assays; immunofluorescence and subcellular fractionation with retroviral complementation

    PMID:22642810 PMID:22832074 PMID:23270877

    Open questions at the time
    • Structural basis of the MMACHC–MMADHC heterodimer not resolved
    • Mechanism of cobalamin handoff to downstream partners unknown
    • Decyanation reaction mechanism at atomic level not defined
  5. 2013 High

    Discovery that methionine synthase is a direct MMACHC-binding partner, with disease mutations R161Q and R206W disrupting this interaction, expanded the processing model from a two-protein relay to a multi-component complex enabling direct cofactor delivery.

    Evidence Co-immunoprecipitation and proximity ligation assay in multiple cell lines with 3D docking models

    PMID:23415655 PMID:23825108

    Open questions at the time
    • Methionine synthase reductase (MSR) role in the complex not yet defined
    • Stoichiometry and assembly order of the full complex unknown
    • Whether complex formation is cobalamin-dependent in cells not established
  6. 2014 High

    Mouse knockout revealed that Mmachc is essential for pre-implantation embryogenesis with haploinsufficiency causing metabolic perturbations, while zebrafish studies placed MMACHC downstream of HCFC1 in craniofacial development, defining in vivo requirements beyond cobalamin metabolism.

    Evidence Gene-trap mouse model with metabolite measurements; zebrafish hcfc1b morpholino with human MMACHC rescue

    PMID:24889031 PMID:25281006

    Open questions at the time
    • Mechanism of MMACHC's role in craniofacial development beyond cobalamin processing unclear
    • Conditional tissue-specific requirements not systematically mapped
    • Whether craniofacial phenotype is cobalamin-dependent or independent not resolved
  7. 2015 High

    Structural resolution of the MMACHC–MMADHC heterodimer by SAXS, together with the finding that Arg161 mutations selectively impair dealkylation while unmasking futile thiol oxidase cycling, provided a mechanistic framework linking genotype to disease severity and oxidative stress.

    Evidence SAXS of 1:1 heterodimer and crystal structure of MMADHC; in vitro dealkylation, decyanation, GSH binding, and thiol oxidase assays with R161Q/R161G mutants

    PMID:25809485 PMID:26483544

    Open questions at the time
    • Atomic-resolution structure of intact MMACHC–MMADHC complex not available
    • In vivo contribution of thiol oxidase activity to patient pathology not quantified
    • Mechanism controlling whether cob(II)alamin enters productive vs. futile cycle not defined
  8. 2016 High

    Identification of MSR–MMACHC and MSR–MMADHC interactions completed the picture of a four-protein cytoplasmic cobalamin processing complex (MMACHC–MMADHC–MS–MSR), where loss of any core member disrupts complex assembly.

    Evidence Co-immunoprecipitation and proximity ligation assays in patient fibroblasts with cblC, cblG, and cblE defects, and siRNA-transfected HepG2 cells

    PMID:27771510

    Open questions at the time
    • Whether complex is constitutive or cobalamin-regulated in vivo unknown
    • No reconstitution of full four-protein complex in vitro
    • Kinetic pathway of cobalamin transfer through complex not defined
  9. 2017 High

    Crystal structures of MMACHC with an antivitamin B12 analogue and characterization of C. elegans CblC defined the active-site architecture for GSH-dependent catalysis and established that thiol oxidase activity proceeds through a glutathionyl-cobalamin intermediate.

    Evidence Crystal structures of human CblC–antivitamin–GSH ternary complex and C. elegans CblC; in vitro thiol oxidase assays with EPR spectroscopy

    PMID:28442570 PMID:28544088

    Open questions at the time
    • No time-resolved structural data capturing catalytic intermediates during dealkylation
    • Physiological regulation of thiol oxidase activity not characterized
    • No structural data for decyanation reaction mechanism
  10. 2018 High

    Discovery that MMACHC can be epigenetically silenced by antisense transcription-induced promoter methylation originating from the adjacent PRDX1 locus, with transgenerational inheritance, established a non-Mendelian mechanism for cblC disease.

    Evidence Bisulfite sequencing, ChIP for H3K36me3, 5-azacytidine rescue of expression, multigenerational pedigree analysis

    PMID:29302025

    Open questions at the time
    • Frequency of epimutation among cblC patients not systematically determined
    • Mechanism of transgenerational epigenetic escape from reprogramming unknown
    • Whether other loci can similarly silence MMACHC not explored
  11. 2020 High

    Extension of MMACHC's substrate repertoire to nitrocobalamin and thiolatocobalamins broadened the catalytic scope and demonstrated that thiolatocobalamins can bypass dealkylation defects in R161 mutants, suggesting therapeutic avenues.

    Evidence In vitro denitration and dethiolation assays with recombinant wild-type and mutant CblC; cell proliferation assays with NO2Cbl

    PMID:32457044 PMID:33190793

    Open questions at the time
    • No cell-based validation of thiolatocobalamin rescue of disease mutations
    • In vivo relevance of nitrocobalamin processing not established
    • Pharmacokinetics of thiolatocobalamins not evaluated
  12. 2023 Medium

    Zebrafish rescue experiments with a cobalamin-binding-deficient MMACHC variant demonstrated that certain craniofacial developmental functions of MMACHC are independent of its cobalamin processing activity, revealing a potential non-canonical role.

    Evidence Zebrafish mmachc mutant rescue with wild-type and cobalamin-binding-deficient MMACHC; chondrocyte morphological analysis

    PMID:37167860

    Open questions at the time
    • Molecular basis of the cobalamin-independent function completely undefined
    • No mammalian validation
    • Binding partners mediating this non-canonical function not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of the full MMACHC–MMADHC–MS–MSR complex, the kinetic mechanism of cobalamin handoff between complex members, the molecular basis of MMACHC's cobalamin-independent developmental roles, and whether therapeutic modulation of the thiol oxidase side reaction can ameliorate cblC disease.
  • No reconstituted in vitro transfer assay for the full four-protein complex
  • Cobalamin-independent function mechanism entirely unknown
  • No structural data for the intact multiprotein processing complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 2
Partners
HCFC1MMADHCMTRMTRR
Complex memberships
MMACHC-MMADHC-MS-MSR cobalamin processing complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 MMACHC was identified as the gene responsible for cblC-type methylmalonic aciduria and homocystinuria; transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype (impaired synthesis of adenosylcobalamin and methylcobalamin), establishing its essential role in intracellular cobalamin processing. Homozygosity mapping, haplotype analysis, mutation identification in 204 patients, retroviral transduction complementation of cblC fibroblasts Nature genetics High 16311595
2009 The MMACHC (cblC) protein catalyzes in vitro and in vivo decyanation of cyanocobalamin (CNCbl) and dealkylation of naturally occurring alkylcobalamins (MeCbl, AdoCbl, and straight-chain alkylcobalamins C2–C6); cblC mutant fibroblasts failed to convert propylcobalamin to AdoCbl or MeCbl, confirming MMACHC is responsible for early processing of both CNCbl and alkylcobalamins in mammalian cells. Radioisotopic (57Co) substrate conversion assays in cultured endothelial cells and patient vs. control skin fibroblasts; in vitro enzymatic assays Molecular genetics and metabolism High 19447654
2009 Wild-type MMACHC binds both OHCbl and CNCbl with similar micromolar affinity (Kd ~5.7 µM) and binds CNCbl in the 'base-off' configuration; NADPH and FAD are required for reductive decyanation of CNCbl to cob(II)alamin. The G147D mutation abolishes binding of both CNCbl and OHCbl (explaining vitamin unresponsiveness), while R161Q retains OHCbl binding but is impaired in CNCbl binding and decyanation (explaining selective OHCbl responsiveness). Recombinant protein binding assays, spectroscopic analysis of base-off CNCbl binding, in vitro decyanation assays with NADPH/FAD, patient mutation analysis Molecular genetics and metabolism High 19700356
2012 Crystal structure of human MMACHC bound to adenosyl-Cbl revealed a nitroreductase scaffold that binds AdoCbl in a 'base-off, five-coordinate' configuration. An arginine-rich pocket (including Arg161) is required for glutathione (GSH) binding and dealkylation activity. MMACHC dimerizes via reciprocal exchange of a conserved 'PNRRP' loop that caps the upper axial ligand in trans and is required for proper dealkylation. Mutation of conserved arginines (including disease-associated Arg161Gln) disrupts GSH binding and dealkylation. X-ray crystallography, solution studies (dimerization triggered by AdoCbl or FMN binding), site-directed mutagenesis, dealkylation activity assays Biochemistry High 22642810
2010 MMACHC protein is thermolabile in its apo form (Tm ~39°C); binding of cobalamins substantially stabilizes the protein (AdoCbl provides the greatest stabilization, ΔTm ~16°C). The late-onset disease mutant R161Q is less thermostable and is less stabilized by cobalamins compared to wild-type, suggesting protein instability as a disease mechanism. Differential scanning fluorimetry, isothermal denaturation of recombinant wild-type and R161Q MMACHC proteins with various cobalamin ligands Molecular genetics and metabolism High 20219402
2010 MMACHC and MMADHC interact directly: MMADHC was confirmed as a binding partner for MMACHC both in vitro (surface plasmon resonance) and in vivo (bacterial two-hybrid). MMACHC binds MeCbl and AdoCbl with higher affinity (Kd ~1.4–1.7 µM) than CNCbl and OHCbl (Kd ~6.4–9.8 µM). Surface plasmon resonance, bacterial two-hybrid, dynamic light scattering, solution-phase intrinsic fluorescence, phage display mapping of binding sites Molecular genetics and metabolism High 21071249
2012 Subcellular fractionation and immunofluorescence established that MMACHC is exclusively cytoplasmic, while MMADHC is both mitochondrial and cytoplasmic, consistent with MMACHC functioning in cytoplasmic cobalamin processing and MMADHC acting as a branch point for cofactor delivery to cytoplasm and mitochondria. Retroviral GFP-tagged MMACHC rescued all biochemical defects in cblC fibroblasts. Immunofluorescence, subcellular fractionation, retroviral complementation of cblC and cblD fibroblasts Molecular genetics and metabolism High 23270877
2012 MMADHC does not bind cobalamin but interacts with MMACHC through its structured C-terminal domain; MMACHC self-association is weaker than its interaction with either MMADHC isoform. Phage display predicted four MMACHC-binding sites on MMADHC, two overlapping with MMACHC self-association sites. Clear-native PAGE, dynamic light scattering, circular dichroism, phage display, surface plasmon resonance Molecular genetics and metabolism High 22832074
2013 CblC (MMACHC) and CblD (MMADHC) form a stable complex particularly under conditions that permit dealkylation of alkylcobalamin by CblC or in the presence of the dealkylated product hydroxocobalamin; CblD functions downstream of CblC and controls cofactor partitioning between cytoplasmic MeCbl and mitochondrial AdoCbl pathways. The CblD N-terminal 115 residues are not required for CblC interaction. Co-immunoprecipitation of complex from fibroblast cell lines, pulldown with CblD variants, limited proteolysis, dealkylation assays Biochimie High 23415655
2013 Methionine synthase (MS) interacts with MMACHC; this interaction is decreased by cblC disease mutations R161Q and R206W in MMACHC as shown by co-immunoprecipitation and proximity ligation assay. 3D modelling showed MS provides a loop making contacts with MMACHC residues R161 and R206. Co-immunoprecipitation, proximity ligation assay (DuoLink), 3D modelling and docking, siRNA knockdown of MS in HEK cells Human molecular genetics High 23825108
2015 Crystal structure of the MMADHC C-terminal region revealed a modified nitroreductase fold with surprising structural homology to MMACHC despite low sequence conservation. MMACHC processes Cbl prior to interaction with MMADHC; patient mutations on both proteins interfere with complex formation. SAXS revealed a 1:1 MMACHC–MMADHC heterodimer where the interaction region overlaps with the MMACHC–Cbl binding site. X-ray crystallography (2.2 Å), small angle X-ray scattering (SAXS), mutagenesis of disease-associated residues, interaction mapping The Journal of biological chemistry High 26483544
2015 Pathogenic missense mutations R161Q (late-onset) and R161G (early-onset) at the same MMACHC residue selectively decrease dealkylation but not decyanation activity, impair glutathione binding, and reduce protein stability. Both mutants exhibit increased futile thiol oxidase cycling (GSH oxidation to GSSG) in the presence of physiological glutathione concentrations, explaining the increased oxidative stress in cblC patients. In vitro enzymatic assays for dealkylation and decyanation, glutathione binding assays, thiol oxidase activity assays, protein stability measurements with purified recombinant proteins The Journal of biological chemistry High 25809485
2016 MS, MSR, MMACHC, and MMADHC form a multiprotein complex in the cytoplasm for intracellular cobalamin processing; novel interactions of MSR with MMACHC and with MMADHC, and MS with MMADHC were identified. Absence of MS or MMACHC expression disrupts interactions among other complex members. Co-immunoprecipitation, DuoLink proximity ligation assays in patient fibroblasts with cblG, cblE, and cblC defects, and siRNA-transfected HepG2 cells Biochimica et biophysica acta. Molecular basis of disease High 27771510
2017 The antivitamin B12 compound F2PhEtyCbl binds human CblC (MMACHC) with high affinity (KD = 130 nM) in the presence of GSH, resists dealkylation by CblC, and stabilizes the ternary CblC–F2PhEtyCbl–GSH complex. The crystal structure of this inactive ternary complex revealed binding interactions between the antivitamin and CblC and the organization of GSH and base-off cobalamin in the active site. Crystal structure of ternary CblC–antivitamin–GSH complex, KD measurement, enzymatic stability assay Angewandte Chemie (International ed. in English) High 28544088
2017 Novel coordination chemistry of CblC-bound cobalamin supports thiol oxidase activity via a glutathionyl-cobalamin intermediate; deglutathionylation by a second GSH molecule yields GSSG. The R161G and R161Q disease mutations in human CblC unmask latent thiol oxidase activity present in wild-type CblC (C. elegans CblC as model). Crystal structure of C. elegans CblC showed architectural differences at the α- and β-faces of cobalamin that promote or suppress this activity. In vitro thiol oxidase activity assays, crystal structure of C. elegans CblC, UV-vis and EPR spectroscopy, mutant CblC characterization The Journal of biological chemistry High 28442570
2018 MMACHC is subject to epigenetic silencing: mutations in the adjacent PRDX1 gene force antisense transcription across the MMACHC locus, generating H3K36me3 marks and promoter hypermethylation (epimutation) that silences MMACHC. 5-azacytidine treatment restored MMACHC expression in fibroblasts. The epimutation was detected in blood, fibroblasts, and sperm and was transmitted across three generations. Bisulfite sequencing, methylation-specific PCR, 5-azacytidine rescue of expression, PRDX1 silencing experiments, ChIP for H3K36me3 Nature communications High 29302025
2009 Epigenetic inactivation (promoter CpG island hypermethylation) of the MMACHC gene causes methionine dependence and a cblC-like cellular phenotype in the MeWo-LC1 melanoma cell line; retroviral infection with wild-type MMACHC corrected the cobalamin metabolism defect and restored growth on homocysteine, establishing that MMACHC loss drives this phenotype. Complementation analysis with cblC fibroblasts, bisulfite sequencing/methylation analysis of CpG island, quantitative PCR, retroviral MMACHC transduction Molecular genetics and metabolism High 19200761
2014 Loss of HCFC1 ortholog hcfc1b in zebrafish causes craniofacial development defects through reduced mmachc expression; craniofacial abnormalities were rescued by expression of human MMACHC, placing MMACHC downstream of HCFC1/HCFC1B in a pathway required for craniofacial development. Zebrafish loss-of-function (hcfc1b morpholino), rescue with human MMACHC expression, neural crest cell differentiation/proliferation assays, human HCFC1 mutation analysis Developmental biology High 25281006
2014 Homozygous gene-trap inactivation of Mmachc in mice is lethal before embryonic day 3.5; heterozygous mice have 50% reduced MMACHC protein and significantly elevated homocysteine and methylmalonic acid, establishing that Mmachc is essential for pre-implantation embryogenesis and demonstrating dose-sensitivity in vivo. Gene-trap mouse model, Western blot for MMACHC protein quantification, metabolite measurements (plasma homocysteine and MMA), blastocyst outgrowth assay Molecular genetics and metabolism High 24889031
2020 CblC (MMACHC) catalyzes GSH-dependent denitration of nitrocobalamin (NO2Cbl) forming 5-coordinate cob(II)alamin; this cob(II)alamin can be oxidized or enter a futile thiol oxidase cycle. CblC also exhibits nitrite reductase activity (converting cob(I)alamin and nitrite to NOCbl). The R161G disease variant stabilizes cob(II)alamin and promotes futile cycling. Denitration activity of CblC supported cell proliferation in the presence of NO2Cbl. In vitro enzymatic assays with purified recombinant CblC, UV-vis spectroscopy, cell proliferation assays in presence of NO2Cbl The Journal of biological chemistry High 32457044
2020 Loss of mmachc function in zebrafish (CRISPR/Cas9 knockout) results in methylmalonic acidemia, severe growth retardation, and lethality in early juvenile life, recapitulating human cblC disease. Retinopathy and thin optic nerves were observed; metabolic and morphological parameters improved with hydroxocobalamin, methylcobalamin, methionine, and betaine supplementation. CRISPR/Cas9 genome editing, metabolite measurements, morphological and retinal phenotyping, fluorescent reporter lines, pharmacological rescue Human molecular genetics High 32186706
2013 The deletion mutation MMACHC-Gln131del (c.392_394del) results in a folded but perturbed protein with reduced enzymatic activity; structural analysis showed Gln131 makes hydrogen bonds to the tail of cobalamin, and its deletion reduces cobalamin binding and enzyme activity as shown by spectroscopic assays on recombinant protein and patient fibroblast studies. Recombinant protein spectroscopic activity assays, circular dichroism spectroscopy, fibroblast complementation studies JIMD reports Medium 23580368
2022 Biophysical analysis of the disease-associated MMACHC-R132X truncation mutant (from c.394C>T) showed it retains secondary structure and remains compact in solution, partly preserving cobalamin binding affinity, consistent with residual function associated with late-onset disease phenotype. Circular dichroism, fluorescence spectroscopy, small angle X-ray scattering (SAXS), molecular dynamics Biochimica et biophysica acta. Proteins and proteomics Medium 35618206
2022 MMACHC transcription is repressed by hypoxia; this repression is partially mediated by HIF1A and the microRNA biogenesis factor DROSHA (whose knockdowns additively released repression), but not through the known HCFC1/THAP11/ZNF143 transcription factor complex. Hypoxia exposure of multiple cell lines and mouse tissues, RT-qPCR, RNA interference against HIF1A, HIF2A, REST, DROSHA Biochimica et biophysica acta. General subjects Medium 35636712
2020 Thiolatocobalamins (cysteaminylcobalamin and 2-mercaptopropionylglycinocobalamin) bind to human CblC and undergo GSH-dependent dethiolation; they can repair the loss of dealkylation activity of pathogenic CblC variants R161G and R161Q, as the spontaneous dethiolation rate is orders of magnitude faster than alkylcobalamin dealkylation. In vitro binding and dethiolation kinetics with purified recombinant wild-type and mutant human CblC, UV-vis spectroscopy Biochimie Medium 33190793
2011 cblC patient fibroblasts show increased export of homocysteine and methylmalonic acid, decreased total intracellular folates, and broad proteome changes (cytoskeletal, neurological, and signaling proteins) compared to controls; hydroxocobalamin supplementation did not restore the proteome to control patterns. 2D-DIGE and LC/ESI/MS proteomics of control vs. cblC fibroblasts, metabolite measurements Molecular genetics and metabolism Medium 21497120
2021 Peripheral retinal neurons do not require intrinsic MMACHC expression for survival and function; conditional deletion of Mmachc in peripheral retinal cells in mice led to accumulation of MMA and folate-cycle intermediates but did not cause retinal morphological or functional defects, suggesting the retinal phenotype in cblC patients is not due to local MMACHC deficiency. Conditional Mmachc knockout mouse (Cre-lox), metabolite quantification in retina, fundus imaging, electroretinography, retinal histology Biochimica et biophysica acta. Molecular basis of disease Medium 34147638
2023 In a zebrafish cblC model (mmachc hg13 mutant), homozygous mutation causes abnormal chondrocyte nuclear organization and increased neighboring cell contacts; both phenotypes were fully rescued by wild-type MMACHC and by a cobalamin-binding–deficient MMACHC variant, indicating these craniofacial defects are independent of cobalamin binding. Zebrafish genetic model, rescue experiments with wild-type and cobalamin-binding mutant MMACHC, chondrocyte morphological analysis, neural crest marker localization Differentiation; research in biological diversity Medium 37167860

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nature genetics 303 16311595
2011 Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. Journal of inherited metabolic disease 176 21748409
2009 Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Human mutation 159 19370762
2014 Clinical presentation and outcome in a series of 88 patients with the cblC defect. Journal of inherited metabolic disease 135 24599607
2006 Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Molecular genetics and metabolism 112 16714133
2009 Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. Molecular genetics and metabolism 102 19447654
2007 Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Molecular genetics and metabolism 81 18164228
2010 Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. Journal of human genetics 80 20631720
2007 Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatric nephrology (Berlin, Germany) 79 17874135
2009 Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Human mutation 76 19760748
2002 Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH. The Journal of biological chemistry 73 12226085
2010 Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China. Journal of inherited metabolic disease 71 20924684
2018 APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nature communications 69 29302025
2007 Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance. American journal of medical genetics. Part A 54 17853453
1999 Molecular cloning and characterization of a novel cbl-family gene, cbl-c. Gene 54 10571044
2009 High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Molecular genetics and metabolism 52 19767224
2005 Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. American journal of kidney diseases : the official journal of the National Kidney Foundation 52 15754282
2004 Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene 52 14661060
2015 Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China. Brain & development 50 26563984
2012 Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped dimer for its B12 processing function. Biochemistry 48 22642810
2018 Upregulation of E3 Ubiquitin Ligase CBLC Enhances EGFR Dysregulation and Signaling in Lung Adenocarcinoma. Cancer research 47 29945960
2010 Thermolability of mutant MMACHC protein in the vitamin B12-responsive cblC disorder. Molecular genetics and metabolism 47 20219402
2009 Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Molecular genetics and metabolism 45 19700356
2019 Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review. European journal of medical genetics 42 31279840
2015 Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking. The Journal of biological chemistry 39 26483544
2010 Interaction between MMACHC and MMADHC, two human proteins participating in intracellular vitamin B₁₂ metabolism. Molecular genetics and metabolism 39 21071249
2014 Hcfc1b, a zebrafish ortholog of HCFC1, regulates craniofacial development by modulating mmachc expression. Developmental biology 36 25281006
2020 Variable phenotypes and outcomes associated with the MMACHC c.609G>A homologous mutation: long term follow-up in a large cohort of cases. Orphanet journal of rare diseases 35 32746869
2015 Pathogenic mutations differentially affect the catalytic activities of the human B12-processing chaperone CblC and increase futile redox cycling. The Journal of biological chemistry 34 25809485
2014 Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene. European journal of pediatrics 34 24853097
2013 The C-terminal domain of CblD interacts with CblC and influences intracellular cobalamin partitioning. Biochimie 34 23415655
2011 The MMACHC proteome: hallmarks of functional cobalamin deficiency in humans. Molecular genetics and metabolism 34 21497120
2010 The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme. The Journal of biological chemistry 34 20525694
2012 A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China. Journal of the neurological sciences 33 22560872
2015 The proteome of cblC defect: in vivo elucidation of altered cellular pathways in humans. Journal of inherited metabolic disease 31 25585586
2022 Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists. Orphanet journal of rare diseases 30 35109910
2018 Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria. BMC medical genetics 30 30157807
2017 Antivitamin B12 Inhibition of the Human B12 -Processing Enzyme CblC: Crystal Structure of an Inactive Ternary Complex with Glutathione as the Cosubstrate. Angewandte Chemie (International ed. in English) 30 28544088
2016 Methionine synthase and methionine synthase reductase interact with MMACHC and with MMADHC. Biochimica et biophysica acta. Molecular basis of disease 29 27771510
2012 Structural features of recombinant MMADHC isoforms and their interactions with MMACHC, proteins of mammalian vitamin B12 metabolism. Molecular genetics and metabolism 29 22832074
2020 The vitamin B12 processing enzyme, mmachc, is essential for zebrafish survival, growth and retinal morphology. Human molecular genetics 27 32186706
2013 Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia. Human molecular genetics 26 23825108
2022 The Follow-Up of Chinese Patients in cblC Type Methylmalonic Acidemia Identified Through Expanded Newborn Screening. Frontiers in genetics 24 35242167
2009 Epigenetic modification of the gene for the vitamin B(12) chaperone MMACHC can result in increased tumorigenicity and methionine dependence. Molecular genetics and metabolism 24 19200761
2017 Coordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblC. The Journal of biological chemistry 22 28442570
2012 Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism. Molecular genetics and metabolism 22 23270877
2010 Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. Pediatric neurology 21 20610126
2015 Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy. Ophthalmic genetics 19 25687216
2014 The Mmachc gene is required for pre-implantation embryogenesis in the mouse. Molecular genetics and metabolism 19 24889031
2020 The human B12 trafficking protein CblC processes nitrocobalamin. The Journal of biological chemistry 18 32457044
2020 Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type. Developmental biology 18 32941884
2012 Cbl-c ubiquitin ligase activity is increased via the interaction of its RING finger domain with a LIM domain of the paxillin homolog, Hic 5. PloS one 18 23145173
2007 Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (CblC type). Journal of inherited metabolic disease 18 17768669
2018 Hydrocephalus in cblC type methylmalonic acidemia. Metabolic brain disease 17 30564975
2024 Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review. Orphanet journal of rare diseases 16 38245797
2017 Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia: A case report and literature review. Medicine 16 29068997
2015 Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity. Oncotarget 16 25883215
2022 Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma. Oncogene 15 35149839
2010 Treatment of cobalamin C (cblC) deficiency during pregnancy. Journal of inherited metabolic disease 15 20830523
2021 PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations. Clinical epigenetics 14 34215320
2013 Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type. JIMD reports 14 23580368
2022 Late-onset cblC deficiency around puberty: a retrospective study of the clinical characteristics, diagnosis, and treatment. Orphanet journal of rare diseases 13 36056359
2021 Methionine dependence in tumor cells: The potential role of cobalamin and MMACHC. Molecular genetics and metabolism 12 33487542
2020 Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC. Biochimie 12 33190793
2019 Loss of function Cbl-c mutations in solid tumors. PloS one 12 31260484
2014 First Chinese case of successful pregnancy with combined methylmalonic aciduria and homocystinuria, cblC type. Brain & development 12 24974159
2011 Expression of Mmachc and Mmadhc during mouse organogenesis. Molecular genetics and metabolism 12 21536470
2011 Combined methylmalonic aciduria and homocystinuria cblC type of a Taiwanese infant with c.609G>A and C.567dupT mutations in the MMACHC gene. Pediatrics and neonatology 12 21835369
2010 Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type. Biochimica et biophysica acta 12 20696242
2022 Epimutations in both the TESK2 and MMACHC promoters in the Epi-cblC inherited disorder of intracellular metabolism of vitamin B12. Clinical epigenetics 11 35440018
2012 Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c. Journal of biochemistry 11 22888118
2022 Intracellular processing of vitamin B12 by MMACHC (CblC). Vitamins and hormones 10 35337623
2019 Noninvasive prenatal diagnosis of cobalamin C (cblC) deficiency through target region sequencing of cell-free DNA in maternal plasma. Prenatal diagnosis 10 31697851
2021 A high frequency and geographical distribution of MMACHC R132* mutation in children with cobalamin C defect. Amino acids 9 33515116
2020 Rapid screening of MMACHC gene mutations by high-resolution melting curve analysis. Molecular genetics & genomic medicine 9 32198913
2015 Prenatal diagnosis using genetic sequencing and identification of a novel mutation in MMACHC. BMC medical genetics 9 26149271
2023 Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort. World journal of pediatrics : WJP 8 38070096
2021 Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying gene c.609G>A mutation. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 8 34704411
2020 Chlorocob(II)alamin Formation Which Enhances the Thiol Oxidase Activity of the B12-Trafficking Protein CblC. Inorganic chemistry 8 33074687
2017 Optical coherence tomography morphology and evolution in cblC disease-related maculopathy in a case series of very young patients. Acta ophthalmologica 8 28481040
2016 Cobalamin C defect-hemolytic uremic syndrome caused by new mutation in MMACHC. Pediatrics international : official journal of the Japan Pediatric Society 8 27324188
2023 Prominent renal complications associated with MMACHC pathogenic variant c.80A > G in Chinese children with cobalamin C deficiency. Frontiers in pediatrics 7 36704130
2022 Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations. Frontiers in genetics 7 35069678
2021 Epimutation of MMACHC compound to a genetic mutation in cblC cases. Molecular genetics & genomic medicine 7 33982424
2023 Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant. Differentiation; research in biological diversity 6 37167860
2022 The human B12 trafficking chaperones: CblA, ATR, CblC and CblD. Methods in enzymology 6 35589192
2022 Investigation on a MMACHC mutant from cblC disease: The c.394C>T variant. Biochimica et biophysica acta. Proteins and proteomics 6 35618206
2022 Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial. Orphanet journal of rare diseases 6 36376887
2021 Absence of MMACHC in peripheral retinal cells does not lead to an ocular phenotype in mice. Biochimica et biophysica acta. Molecular basis of disease 6 34147638
2015 The Ubiquitin Ligase CBLC Maintains the Network Organization of the Golgi Apparatus. PloS one 6 26393512
2009 Abnormal mammary gland development in MMTV-CBLC transgenic mouse. In vivo (Athens, Greece) 6 19414407
2024 Clinical and electroencephalogram characteristics of methylmalonic acidemia with MMACHC and MUT gene mutations. BMC pediatrics 5 38355526
2023 Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency? Molecular genetics and metabolism 5 37604084
2022 CBLC inhibits the proliferation and metastasis of breast cancer cells via ubiquitination and degradation of CTTN. Journal of receptor and signal transduction research 5 36043996
2020 Generation of a Human iPSC line (SDQLCHi021-A) from a patient with methylmalonic acidemia cblC type carrying compound heterozygous mutations in MMAHC gene. Stem cell research 5 32058304
2020 Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing. Human molecular genetics 5 32068834
2015 Genetic analysis of four cases of methylmalonic aciduria and homocystinuria, cblC type#. International journal of clinical and experimental pathology 5 26464686
2001 Characterization of the mouse Cblc/Cbl3 gene. Biochemical and biophysical research communications 5 11162497
1991 Metabolic cooperation among cell lines from patients with inborn errors of vitamin B12 metabolism: differential response of cblC and cblD. Clinical and investigative medicine. Medecine clinique et experimentale 5 1676355
2022 HIF1 and DROSHA are involved in MMACHC repression in hypoxia. Biochimica et biophysica acta. General subjects 4 35636712