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Protein

Methylmalonic aciduria and homocystinuria type C protein

Gene

MMACHC

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

    • cobalamin binding Source: UniProtKB-KW
    • cyanocobalamin reductase (cyanide-eliminating) activity Source: UniProtKB
    • demethylase activity Source: UniProtKB
    • FAD binding Source: UniProtKB
    • glutathione binding Source: UniProtKB
    • oxidoreductase activity Source: UniProtKB
    • protein homodimerization activity Source: UniProtKB

    GO - Biological processi

    • cobalamin biosynthetic process Source: UniProtKB
    • cobalamin metabolic process Source: UniProtKB
    • demethylation Source: UniProtKB
    • glutathione metabolic process Source: UniProtKB
    • oxidation-reduction process Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Ligandi

    Cobalamin, Cobalt, FAD, Flavoprotein, FMN, NADP

    Enzyme and pathway databases

    BioCyciZFISH: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.
    UniPathwayiUPA00148.

    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

    HGNCiHGNC:24525. MMACHC.

    Subcellular locationi

    GO - Cellular componenti

    • cytoplasm Source: UniProtKB
    • cytosol Source: Reactome
    • mitochondrion Source: Ensembl
    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Involvement in diseasei

    Methylmalonic aciduria and homocystinuria type cblC (MMAHCC)3 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA 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 MMAHCC. 1 PublicationCorresponds to variant rs546099787dbSNPEnsembl.1
    Natural variantiVAR_024771116L → P in MMAHCC. 1 PublicationCorresponds to variant rs121918240dbSNPEnsembl.1
    Natural variantiVAR_024772122H → R in MMAHCC. 1 Publication1
    Natural variantiVAR_024773130Y → H in MMAHCC. 1 PublicationCorresponds to variant rs372670428dbSNPEnsembl.1
    Natural variantiVAR_024774147G → A in MMAHCC. 1 PublicationCorresponds to variant rs140522266dbSNPEnsembl.1
    Natural variantiVAR_024775147G → D in MMAHCC; loss of cyanocobalamin binding. 2 PublicationsCorresponds to variant rs140522266dbSNPEnsembl.1
    Natural variantiVAR_024776156G → D in MMAHCC. 1 Publication1
    Natural variantiVAR_024777157W → C in MMAHCC. 1 Publication1
    Natural variantiVAR_024778161R → G in MMAHCC; results in decreased stability and decreased methylcobalamin dealkylation activity. 2 Publications1
    Natural variantiVAR_024779161R → Q in MMAHCC; 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 rs121918243dbSNPEnsembl.1
    Natural variantiVAR_024780189R → S in MMAHCC. 1 PublicationCorresponds to variant rs200895671dbSNPEnsembl.1
    Natural variantiVAR_024781193L → P in MMAHCC. 1 Publication1
    Natural variantiVAR_024782206R → P in MMAHCC. 1 Publication1
    Natural variantiVAR_024783206R → W in MMAHCC. 1 Publication1

    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.
    MalaCardsiMMACHC.
    MIMi277400. phenotype.
    603174. 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.
    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.
    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 homodimerization activity Source: UniProtKB

    Protein-protein interaction databases

    BioGridi117458. 3 interactors.
    IntActiQ9Y4U1. 1 interactor.
    STRINGi9606.ENSP00000383840.

    Structurei

    Secondary structure

    1282
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi3 – 16Combined sources14
    Helixi17 – 19Combined sources3
    Beta strandi21 – 27Combined sources7
    Helixi28 – 32Combined sources5
    Helixi37 – 39Combined sources3
    Beta strandi47 – 54Combined sources8
    Helixi58 – 61Combined sources4
    Helixi63 – 66Combined sources4
    Beta strandi74 – 76Combined sources3
    Helixi78 – 93Combined sources16
    Beta strandi100 – 103Combined sources4
    Helixi104 – 106Combined sources3
    Beta strandi113 – 115Combined sources3
    Helixi117 – 123Combined sources7
    Beta strandi126 – 130Combined sources5
    Helixi132 – 134Combined sources3
    Beta strandi135 – 137Combined sources3
    Turni139 – 142Combined sources4
    Beta strandi148 – 151Combined sources4
    Turni152 – 154Combined sources3
    Beta strandi159 – 170Combined sources12
    Helixi186 – 198Combined sources13
    Helixi200 – 202Combined sources3
    Helixi204 – 207Combined sources4
    Helixi217 – 222Combined sources6
    Helixi226 – 229Combined sources4
    Turni235 – 237Combined sources3

    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[»]
    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.
    OMAiLSTPSMF.
    OrthoDBiEOG091G0GLW.
    PhylomeDBiQ9Y4U1.
    TreeFamiTF332476.

    Family and domain databases

    CDDicd12959. MMACHC-like. 1 hit.
    InterProiIPR032037. MMACHC.
    [Graphical view]
    PANTHERiPTHR31457. PTHR31457. 1 hit.
    PfamiPF16690. MMACHC. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    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

    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 MMAHCC. 1 PublicationCorresponds to variant rs546099787dbSNPEnsembl.1
    Natural variantiVAR_024771116L → P in MMAHCC. 1 PublicationCorresponds to variant rs121918240dbSNPEnsembl.1
    Natural variantiVAR_024772122H → R in MMAHCC. 1 Publication1
    Natural variantiVAR_024773130Y → H in MMAHCC. 1 PublicationCorresponds to variant rs372670428dbSNPEnsembl.1
    Natural variantiVAR_024774147G → A in MMAHCC. 1 PublicationCorresponds to variant rs140522266dbSNPEnsembl.1
    Natural variantiVAR_024775147G → D in MMAHCC; loss of cyanocobalamin binding. 2 PublicationsCorresponds to variant rs140522266dbSNPEnsembl.1
    Natural variantiVAR_024776156G → D in MMAHCC. 1 Publication1
    Natural variantiVAR_024777157W → C in MMAHCC. 1 Publication1
    Natural variantiVAR_024778161R → G in MMAHCC; results in decreased stability and decreased methylcobalamin dealkylation activity. 2 Publications1
    Natural variantiVAR_024779161R → Q in MMAHCC; 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 rs121918243dbSNPEnsembl.1
    Natural variantiVAR_024780189R → S in MMAHCC. 1 PublicationCorresponds to variant rs200895671dbSNPEnsembl.1
    Natural variantiVAR_024781193L → P in MMAHCC. 1 Publication1
    Natural variantiVAR_024782206R → P in MMAHCC. 1 Publication1
    Natural variantiVAR_024783206R → W in MMAHCC. 1 Publication1
    Natural variantiVAR_038805271S → G.Corresponds to variant rs35219601dbSNPEnsembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL080062 mRNA. Translation: CAB45693.2.
    AL451136 Genomic DNA. Translation: CAI13094.1.
    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.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL080062 mRNA. Translation: CAB45693.2.
    AL451136 Genomic DNA. Translation: CAI13094.1.
    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[»]
    ProteinModelPortaliQ9Y4U1.
    SMRiQ9Y4U1.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi117458. 3 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.
    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.
    GeneCardsiMMACHC.
    GeneReviewsiMMACHC.
    H-InvDBHIX0000532.
    HGNCiHGNC:24525. MMACHC.
    HPAiHPA027394.
    HPA027399.
    HPA027402.
    MalaCardsiMMACHC.
    MIMi277400. phenotype.
    603174. 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.
    OMAiLSTPSMF.
    OrthoDBiEOG091G0GLW.
    PhylomeDBiQ9Y4U1.
    TreeFamiTF332476.

    Enzyme and pathway databases

    UniPathwayiUPA00148.
    BioCyciZFISH: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.
    PROiQ9Y4U1.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000132763.
    CleanExiHS_MMACHC.
    ExpressionAtlasiQ9Y4U1. baseline and differential.
    GenevisibleiQ9Y4U1. HS.

    Family and domain databases

    CDDicd12959. MMACHC-like. 1 hit.
    InterProiIPR032037. MMACHC.
    [Graphical view]
    PANTHERiPTHR31457. PTHR31457. 1 hit.
    PfamiPF16690. MMACHC. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiMMAC_HUMAN
    AccessioniPrimary (citable) accession number: Q9Y4U1
    Secondary accession number(s): Q5T157, Q9BRQ7
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: January 10, 2006
    Last sequence update: January 10, 2006
    Last modified: November 30, 2016
    This is version 121 of the entry and version 3 of the sequence. [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. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.