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Protein

Methylmalonic aciduria and homocystinuria type C protein

Gene

MMACHC

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalyzes the reductive dealkylation of cyanocobalamin to cob(II)alamin, using FAD or FMN as cofactor and NADPH as cosubstrate (PubMed:19700356, PubMed:21697092, PubMed:22642810). Can also catalyze the glutathione-dependent reductive demethylation of methylcobalamin, and, with much lower efficiency, the glutathione-dependent reductive demethylation of adenosylcobalamin (PubMed:19801555, PubMed:22642810, PubMed:25809485). Under anaerobic conditions cob(I)alamin is the first product; it is highly reactive and is converted to aquocob(II)alamin in the presence of oxygen (PubMed:19801555). Binds cyanocobalamin, adenosylcobalamin, methylcobalamin and other, related vitamin B12 derivatives (PubMed:21071249).6 Publications

Cofactori

FAD2 Publications, FMN2 PublicationsNote: Can utilize both FAD and FMN.2 Publications

Kineticsi

  1. KM=27.7 µM for glutathione1 Publication

    Pathwayi: adenosylcobalamin biosynthesis

    This protein is involved in the pathway adenosylcobalamin biosynthesis, which is part of Cofactor biosynthesis.3 Publications
    View all proteins of this organism that are known to be involved in the pathway adenosylcobalamin biosynthesis and in Cofactor biosynthesis.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei104SubstrateCombined sources2 Publications1
    Binding sitei149Substrate; via amide nitrogenCombined sources2 Publications1
    Binding sitei160Substrate; via amide nitrogen and carbonyl oxygenCombined sources2 Publications1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionOxidoreductase
    LigandCobalamin, Cobalt, FAD, Flavoprotein, FMN, NADP

    Enzyme and pathway databases

    BioCyciMetaCyc:ENSG00000132763-MONOMER
    ReactomeiR-HSA-196741 Cobalamin (Cbl, vitamin B12) transport and metabolism
    R-HSA-3359473 Defective MMADHC causes methylmalonic aciduria and homocystinuria type cblD
    R-HSA-3359474 Defective MMACHC causes methylmalonic aciduria and homocystinuria type cblC
    UniPathwayi
    UPA00148

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Methylmalonic aciduria and homocystinuria type C protein (EC:1.16.1.-3 Publications)
    Alternative name(s):
    CblC2 Publications
    Cyanocobalamin reductase (cyanide-eliminating)
    Gene namesi
    Name:MMACHC
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 1

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000132763.14
    HGNCiHGNC:24525 MMACHC
    MIMi609831 gene
    neXtProtiNX_Q9Y4U1

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Involvement in diseasei

    Methylmalonic aciduria and homocystinuria, cblC type (MAHCC)5 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionAn autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood.
    See also OMIM:277400
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_02477027Q → R in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs546099787EnsemblClinVar.1
    Natural variantiVAR_024771116L → P in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs121918240EnsemblClinVar.1
    Natural variantiVAR_024772122H → R in MAHCC. 1 Publication1
    Natural variantiVAR_024773130Y → H in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs372670428Ensembl.1
    Natural variantiVAR_024774147G → A in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs140522266EnsemblClinVar.1
    Natural variantiVAR_024775147G → D in MAHCC; loss of cyanocobalamin binding. 2 PublicationsCorresponds to variant dbSNP:rs140522266EnsemblClinVar.1
    Natural variantiVAR_024776156G → D in MAHCC. 1 Publication1
    Natural variantiVAR_024777157W → C in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs1002571805Ensembl.1
    Natural variantiVAR_024778161R → G in MAHCC; results in decreased stability and decreased methylcobalamin dealkylation activity. 2 Publications1
    Natural variantiVAR_024779161R → Q in MAHCC; results in decreased stability and reduced stabilization induced by cobalamin binding; has reduced affinity for cyanocobalamin and reduced activity in dealkylation of methylcobalamin. 5 PublicationsCorresponds to variant dbSNP:rs121918243EnsemblClinVar.1
    Natural variantiVAR_024780189R → S in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs200895671EnsemblClinVar.1
    Natural variantiVAR_024781193L → P in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs1233135084Ensembl.1
    Natural variantiVAR_024782206R → P in MAHCC. 1 Publication1
    Natural variantiVAR_024783206R → W in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs538023671EnsemblClinVar.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi122H → A: Reduced affinity for cyanocobalamin. 1 Publication1
    Mutagenesisi206R → Q: Impairs protein folding. 1 Publication1
    Mutagenesisi230R → Q: Reduced activity in dealkylation of methylcobalamin. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi25974
    GeneReviewsiMMACHC
    MalaCardsiMMACHC
    MIMi277400 phenotype
    OpenTargetsiENSG00000132763
    Orphaneti79282 Methylmalonic acidemia with homocystinuria, type cblC
    PharmGKBiPA142671348

    Chemistry databases

    DrugBankiDB00115 Cyanocobalamin
    DB00200 Hydroxocobalamin

    Polymorphism and mutation databases

    BioMutaiMMACHC
    DMDMi85681045

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000762581 – 282Methylmalonic aciduria and homocystinuria type C proteinAdd BLAST282

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei245PhosphoserineCombined sources1
    Modified residuei247PhosphoserineCombined sources1
    Modified residuei275PhosphoserineCombined sources1
    Modified residuei279PhosphoserineCombined sources1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    EPDiQ9Y4U1
    MaxQBiQ9Y4U1
    PaxDbiQ9Y4U1
    PeptideAtlasiQ9Y4U1
    PRIDEiQ9Y4U1
    ProteomicsDBi86249
    TopDownProteomicsiQ9Y4U1

    PTM databases

    iPTMnetiQ9Y4U1
    PhosphoSitePlusiQ9Y4U1

    Expressioni

    Tissue specificityi

    Widely expressed. Expressed at higher level in fetal liver. Also expressed in spleen, lymph node, thymus and bone marrow. Weakly or not expressed in peripheral blood leukocytes.1 Publication

    Gene expression databases

    BgeeiENSG00000132763 Expressed in 129 organ(s), highest expression level in testis
    CleanExiHS_MMACHC
    ExpressionAtlasiQ9Y4U1 baseline and differential
    GenevisibleiQ9Y4U1 HS

    Organism-specific databases

    HPAiHPA027394
    HPA027399
    HPA027402

    Interactioni

    Subunit structurei

    Monomer in the absence of bound substrate (PubMed:21697092, PubMed:22642810). Homodimer; dimerization is triggered by binding to FMN or adenosylcobalamin (PubMed:22642810). Heterodimer with MMADHC (PubMed:21071249, PubMed:23415655, PubMed:26483544).4 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    MTRQ997073EBI-9775184,EBI-1045782

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi117458, 6 interactors
    IntActiQ9Y4U1, 1 interactor
    STRINGi9606.ENSP00000383840

    Structurei

    Secondary structure

    1282
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliQ9Y4U1
    SMRiQ9Y4U1
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9Y4U1

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni115 – 118Substrate bindingCombined sources2 Publications4
    Regioni129 – 131Substrate bindingCombined sources2 Publications3

    Sequence similaritiesi

    Belongs to the MMACHC family.Curated

    Phylogenomic databases

    eggNOGiENOG410IKBC Eukaryota
    ENOG410XTCP LUCA
    GeneTreeiENSGT00390000003464
    HOGENOMiHOG000231413
    HOVERGENiHBG080267
    InParanoidiQ9Y4U1
    KOiK14618
    OMAiMEPQVAE
    OrthoDBiEOG091G0GLW
    PhylomeDBiQ9Y4U1
    TreeFamiTF332476

    Family and domain databases

    CDDicd12959 MMACHC-like, 1 hit
    InterProiView protein in InterPro
    IPR032037 MMACHC
    PANTHERiPTHR31457 PTHR31457, 1 hit
    PfamiView protein in Pfam
    PF16690 MMACHC, 1 hit

    Sequence (1+)i

    Sequence statusi: Complete.

    This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

    Q9Y4U1-1 [UniParc]FASTAAdd to basket
    « Hide
            10         20         30         40         50
    MEPKVAELKQ KIEDTLCPFG FEVYPFQVAW YNELLPPAFH LPLPGPTLAF
    60 70 80 90 100
    LVLSTPAMFD RALKPFLQSC HLRMLTDPVD QCVAYHLGRV RESLPELQIE
    110 120 130 140 150
    IIADYEVHPN RRPKILAQTA AHVAGAAYYY QRQDVEADPW GNQRISGVCI
    160 170 180 190 200
    HPRFGGWFAI RGVVLLPGIE VPDLPPRKPH DCVPTRADRI ALLEGFNFHW
    210 220 230 240 250
    RDWTYRDAVT PQERYSEEQK AYFSTPPAQR LALLGLAQPS EKPSSPSPDL
    260 270 280
    PFTTPAPKKP GNPSRARSWL SPRVSPPASP GP
    Length:282
    Mass (Da):31,728
    Last modified:January 10, 2006 - v3
    Checksum:i3A7E6BC774CB5D17
    GO

    Computationally mapped potential isoform sequencesi

    There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    A0A0C4DGU2A0A0C4DGU2_HUMAN
    Methylmalonic aciduria and homocyst...
    MMACHC
    225Annotation score:

    Sequence cautioni

    The sequence AAH06122 differs from that shown. Reason: Erroneous initiation.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti100E → G in CAB45693 (PubMed:17974005).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_02477027Q → R in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs546099787EnsemblClinVar.1
    Natural variantiVAR_024771116L → P in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs121918240EnsemblClinVar.1
    Natural variantiVAR_024772122H → R in MAHCC. 1 Publication1
    Natural variantiVAR_024773130Y → H in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs372670428Ensembl.1
    Natural variantiVAR_024774147G → A in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs140522266EnsemblClinVar.1
    Natural variantiVAR_024775147G → D in MAHCC; loss of cyanocobalamin binding. 2 PublicationsCorresponds to variant dbSNP:rs140522266EnsemblClinVar.1
    Natural variantiVAR_024776156G → D in MAHCC. 1 Publication1
    Natural variantiVAR_024777157W → C in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs1002571805Ensembl.1
    Natural variantiVAR_024778161R → G in MAHCC; results in decreased stability and decreased methylcobalamin dealkylation activity. 2 Publications1
    Natural variantiVAR_024779161R → Q in MAHCC; results in decreased stability and reduced stabilization induced by cobalamin binding; has reduced affinity for cyanocobalamin and reduced activity in dealkylation of methylcobalamin. 5 PublicationsCorresponds to variant dbSNP:rs121918243EnsemblClinVar.1
    Natural variantiVAR_024780189R → S in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs200895671EnsemblClinVar.1
    Natural variantiVAR_024781193L → P in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs1233135084Ensembl.1
    Natural variantiVAR_024782206R → P in MAHCC. 1 Publication1
    Natural variantiVAR_024783206R → W in MAHCC. 1 PublicationCorresponds to variant dbSNP:rs538023671EnsemblClinVar.1
    Natural variantiVAR_038805271S → G. Corresponds to variant dbSNP:rs35219601EnsemblClinVar.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL080062 mRNA Translation: CAB45693.2
    AL451136 Genomic DNA No translation available.
    BC006122 mRNA Translation: AAH06122.3 Different initiation.
    CCDSiCCDS41324.1
    PIRiT12462
    RefSeqiNP_001317469.1, NM_001330540.1
    NP_056321.2, NM_015506.2
    UniGeneiHs.13024

    Genome annotation databases

    EnsembliENST00000401061; ENSP00000383840; ENSG00000132763
    GeneIDi25974
    KEGGihsa:25974
    UCSCiuc009vxv.4 human

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL080062 mRNA Translation: CAB45693.2
    AL451136 Genomic DNA No translation available.
    BC006122 mRNA Translation: AAH06122.3 Different initiation.
    CCDSiCCDS41324.1
    PIRiT12462
    RefSeqiNP_001317469.1, NM_001330540.1
    NP_056321.2, NM_015506.2
    UniGeneiHs.13024

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3SBYX-ray2.71A/B1-244[»]
    3SBZX-ray2.00A1-244[»]
    3SC0X-ray1.95A1-238[»]
    3SOMX-ray2.40A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P1-282[»]
    5UOSX-ray2.51A1-238[»]
    ProteinModelPortaliQ9Y4U1
    SMRiQ9Y4U1
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi117458, 6 interactors
    IntActiQ9Y4U1, 1 interactor
    STRINGi9606.ENSP00000383840

    Chemistry databases

    DrugBankiDB00115 Cyanocobalamin
    DB00200 Hydroxocobalamin

    PTM databases

    iPTMnetiQ9Y4U1
    PhosphoSitePlusiQ9Y4U1

    Polymorphism and mutation databases

    BioMutaiMMACHC
    DMDMi85681045

    Proteomic databases

    EPDiQ9Y4U1
    MaxQBiQ9Y4U1
    PaxDbiQ9Y4U1
    PeptideAtlasiQ9Y4U1
    PRIDEiQ9Y4U1
    ProteomicsDBi86249
    TopDownProteomicsiQ9Y4U1

    Protocols and materials databases

    DNASUi25974
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000401061; ENSP00000383840; ENSG00000132763
    GeneIDi25974
    KEGGihsa:25974
    UCSCiuc009vxv.4 human

    Organism-specific databases

    CTDi25974
    DisGeNETi25974
    EuPathDBiHostDB:ENSG00000132763.14
    GeneCardsiMMACHC
    GeneReviewsiMMACHC
    H-InvDBiHIX0000532
    HGNCiHGNC:24525 MMACHC
    HPAiHPA027394
    HPA027399
    HPA027402
    MalaCardsiMMACHC
    MIMi277400 phenotype
    609831 gene
    neXtProtiNX_Q9Y4U1
    OpenTargetsiENSG00000132763
    Orphaneti79282 Methylmalonic acidemia with homocystinuria, type cblC
    PharmGKBiPA142671348
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiENOG410IKBC Eukaryota
    ENOG410XTCP LUCA
    GeneTreeiENSGT00390000003464
    HOGENOMiHOG000231413
    HOVERGENiHBG080267
    InParanoidiQ9Y4U1
    KOiK14618
    OMAiMEPQVAE
    OrthoDBiEOG091G0GLW
    PhylomeDBiQ9Y4U1
    TreeFamiTF332476

    Enzyme and pathway databases

    UniPathwayi
    UPA00148

    BioCyciMetaCyc:ENSG00000132763-MONOMER
    ReactomeiR-HSA-196741 Cobalamin (Cbl, vitamin B12) transport and metabolism
    R-HSA-3359473 Defective MMADHC causes methylmalonic aciduria and homocystinuria type cblD
    R-HSA-3359474 Defective MMACHC causes methylmalonic aciduria and homocystinuria type cblC

    Miscellaneous databases

    ChiTaRSiMMACHC human
    EvolutionaryTraceiQ9Y4U1
    GeneWikiiMMACHC
    GenomeRNAii25974
    PROiPR:Q9Y4U1
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000132763 Expressed in 129 organ(s), highest expression level in testis
    CleanExiHS_MMACHC
    ExpressionAtlasiQ9Y4U1 baseline and differential
    GenevisibleiQ9Y4U1 HS

    Family and domain databases

    CDDicd12959 MMACHC-like, 1 hit
    InterProiView protein in InterPro
    IPR032037 MMACHC
    PANTHERiPTHR31457 PTHR31457, 1 hit
    PfamiView protein in Pfam
    PF16690 MMACHC, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiMMAC_HUMAN
    AccessioniPrimary (citable) accession number: Q9Y4U1
    Secondary accession number(s): Q5T157, Q9BRQ7
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 10, 2006
    Last sequence update: January 10, 2006
    Last modified: October 10, 2018
    This is version 134 of the entry and version 3 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 1
      Human chromosome 1: entries, gene names and cross-references to MIM
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families
    4. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    5. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    6. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    7. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health

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