GenomeNet

Database: UniProt
Entry: MMAC_DANRE
LinkDB: MMAC_DANRE
Original site: MMAC_DANRE 
ID   MMAC_DANRE              Reviewed;         250 AA.
AC   Q5RFU5;
DT   10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT   10-JAN-2006, sequence version 2.
DT   27-MAR-2024, entry version 86.
DE   RecName: Full=Cyanocobalamin reductase / alkylcobalamin dealkylase;
DE   AltName: Full=Alkylcobalamin:glutathione S-alkyltransferase;
DE            EC=2.5.1.151 {ECO:0000250|UniProtKB:Q9Y4U1};
DE   AltName: Full=CblC;
DE   AltName: Full=Cyanocobalamin reductase (cyanide-eliminating);
DE            EC=1.16.1.6 {ECO:0000250|UniProtKB:Q9Y4U1};
DE   AltName: Full=Methylmalonic aciduria and homocystinuria type C protein;
DE            Short=MMACHC;
GN   Name=mmachc; ORFNames=si:zfos-47c12.1;
OS   Danio rerio (Zebrafish) (Brachydanio rerio).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC   Danionidae; Danioninae; Danio.
OX   NCBI_TaxID=7955;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Tuebingen;
RX   PubMed=23594743; DOI=10.1038/nature12111;
RA   Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA   Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA   Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA   White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA   Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA   Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA   Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA   Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA   Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA   Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA   Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA   Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA   Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA   Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA   Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA   McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA   Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA   Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA   Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA   Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA   Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA   Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA   Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA   Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA   Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA   Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA   Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA   Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA   de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA   Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT   "The zebrafish reference genome sequence and its relationship to the human
RT   genome.";
RL   Nature 496:498-503(2013).
CC   -!- FUNCTION: Cobalamin (vitamin B12) cytosolic chaperone that catalyzes
CC       the reductive decyanation of cyanocob(III)alamin (cyanocobalamin,
CC       CNCbl) to yield cob(II)alamin and cyanide, using FAD or FMN as
CC       cofactors and NADPH as cosubstrate. Cyanocobalamin constitutes the
CC       inactive form of vitamin B12 introduced from the diet, and is converted
CC       into the active cofactors methylcobalamin (MeCbl) involved in
CC       methionine biosynthesis, and 5'-deoxyadenosylcobalamin (AdoCbl)
CC       involved in the TCA cycle. Forms a complex with the lysosomal
CC       transporter ABCD4 and its chaperone LMBRD1, to transport cobalamin
CC       across the lysosomal membrane into the cytosol. The processing of
CC       cobalamin in the cytosol occurs in a multiprotein complex composed of
CC       at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR
CC       (methionine synthase) which may contribute to shuttle safely and
CC       efficiently cobalamin towards MTR in order to produce methionine. Also
CC       acts as a glutathione transferase by catalyzing the dealkylation of the
CC       alkylcob(III)alamins MeCbl and AdoCbl, using the thiolate of
CC       glutathione for nucleophilic displacement to generate cob(I)alamin and
CC       the corresponding glutathione thioether. The conversion of incoming
CC       MeCbl or AdoCbl into a common intermediate cob(I)alamin is necessary to
CC       meet the cellular needs for both cofactors. Cysteine and homocysteine
CC       cannot substitute for glutathione in this reaction.
CC       {ECO:0000250|UniProtKB:Q9Y4U1}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=2 cob(II)alamin-[cyanocobalamin reductase] + 2 hydrogen
CC         cyanide + NADP(+) = 2 apo-[cyanocobalamin reductase] + 2
CC         cyanocob(III)alamin + H(+) + NADPH; Xref=Rhea:RHEA:16113, Rhea:RHEA-
CC         COMP:14717, Rhea:RHEA-COMP:14718, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16304, ChEBI:CHEBI:17439, ChEBI:CHEBI:18407,
CC         ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:83228; EC=1.16.1.6;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:16115;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=an R-cob(III)alamin + apo-[alkylcobalamin reductase] +
CC         glutathione = an S-substituted glutathione + cob(I)alamin-
CC         [alkylcobalamin reductase] + H(+); Xref=Rhea:RHEA:40719, Rhea:RHEA-
CC         COMP:14730, Rhea:RHEA-COMP:14731, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:57925, ChEBI:CHEBI:60488, ChEBI:CHEBI:83228,
CC         ChEBI:CHEBI:90779, ChEBI:CHEBI:140785; EC=2.5.1.151;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40720;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=apo-[alkylcobalamin reductase] + glutathione +
CC         methylcob(III)alamin = cob(I)alamin-[alkylcobalamin reductase] + H(+)
CC         + S-methyl glutathione; Xref=Rhea:RHEA:63132, Rhea:RHEA-COMP:14730,
CC         Rhea:RHEA-COMP:14731, ChEBI:CHEBI:15378, ChEBI:CHEBI:28115,
CC         ChEBI:CHEBI:57925, ChEBI:CHEBI:60488, ChEBI:CHEBI:83228,
CC         ChEBI:CHEBI:141467; EC=2.5.1.151;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63133;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=adenosylcob(III)alamin + apo-[alkylcobalamin reductase] +
CC         glutathione = cob(I)alamin-[alkylcobalamin reductase] + H(+) + S-
CC         adenosylglutathione; Xref=Rhea:RHEA:63136, Rhea:RHEA-COMP:14730,
CC         Rhea:RHEA-COMP:14731, ChEBI:CHEBI:15378, ChEBI:CHEBI:18408,
CC         ChEBI:CHEBI:57925, ChEBI:CHEBI:60488, ChEBI:CHEBI:83228,
CC         ChEBI:CHEBI:146184; EC=2.5.1.151;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63137;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC       Name=FMN; Xref=ChEBI:CHEBI:58210;
CC         Evidence={ECO:0000250|UniProtKB:Q9Y4U1};
CC       Note=Can utilize both FAD and FMN. {ECO:0000250|UniProtKB:Q9Y4U1};
CC   -!- SUBUNIT: Monomer in the absence of bound substrate. Homodimer;
CC       dimerization is triggered by binding to FMN or adenosylcobalamin.
CC       Heterodimer with MMADHC. {ECO:0000250|UniProtKB:Q9Y4U1}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC       {ECO:0000250|UniProtKB:Q9Y4U1}.
CC   -!- SIMILARITY: Belongs to the MMACHC family. {ECO:0000305}.
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DR   EMBL; CR854946; CAI12067.1; -; Genomic_DNA.
DR   RefSeq; NP_001108361.2; NM_001114889.2.
DR   AlphaFoldDB; Q5RFU5; -.
DR   SMR; Q5RFU5; -.
DR   STRING; 7955.ENSDARP00000117903; -.
DR   PaxDb; 7955-ENSDARP00000117903; -.
DR   GeneID; 555267; -.
DR   KEGG; dre:555267; -.
DR   AGR; ZFIN:ZDB-GENE-030131-3167; -.
DR   CTD; 25974; -.
DR   ZFIN; ZDB-GENE-030131-3167; mmachc.
DR   eggNOG; KOG4552; Eukaryota.
DR   InParanoid; Q5RFU5; -.
DR   OrthoDB; 3035512at2759; -.
DR   PhylomeDB; Q5RFU5; -.
DR   Reactome; R-DRE-9759218; Cobalamin (Cbl) metabolism.
DR   PRO; PR:Q5RFU5; -.
DR   Proteomes; UP000000437; Chromosome 20.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-KW.
DR   GO; GO:0033787; F:cyanocobalamin reductase (cyanide-eliminating) activity; IBA:GO_Central.
DR   GO; GO:0032451; F:demethylase activity; IBA:GO_Central.
DR   GO; GO:0071949; F:FAD binding; IBA:GO_Central.
DR   GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR   GO; GO:0009235; P:cobalamin metabolic process; IBA:GO_Central.
DR   GO; GO:0048703; P:embryonic viscerocranium morphogenesis; IMP:ZFIN.
DR   CDD; cd12959; MMACHC-like; 1.
DR   InterPro; IPR032037; MMACHC.
DR   PANTHER; PTHR31457:SF2; CYANOCOBALAMIN REDUCTASE _ ALKYLCOBALAMIN DEALKYLASE; 1.
DR   PANTHER; PTHR31457; METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA TYPE C PROTEIN; 1.
DR   Pfam; PF16690; MMACHC; 1.
PE   3: Inferred from homology;
KW   Cobalamin; Cobalt; Cytoplasm; FAD; Flavoprotein; FMN; NADP; Oxidoreductase;
KW   Phosphoprotein; Reference proteome; Transferase.
FT   CHAIN           1..250
FT                   /note="Cyanocobalamin reductase / alkylcobalamin
FT                   dealkylase"
FT                   /id="PRO_0000076261"
FT   BINDING         108
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT   BINDING         119..122
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT   BINDING         133..135
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT   BINDING         153
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT   BINDING         164
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
SQ   SEQUENCE   250 AA;  28716 MW;  F794C76F1D361B0D CRC64;
     MAISSERVEE LLRTFRESLK AKGFEIYPFK VGWYNAVLTA AHHLQYPADT LAVLVISTPA
     MFECAFLPFL QSQSCESLRD PIDQCTAHTL SACISLCFAN QFVDVSYDYE MLPSRKPKFL
     AQTAAHVSGA AYYYQTSDIH NPPWGEKKMF GVCVHPQLGG WFAIRALLVF RDVQAGAGFQ
     QRDPADCVCT QEERIRLLES FNLRWRDWSY RDIVPAEDRY SDQQKQYFIT PPGQRRALLR
     QWGYLTDTQS
//
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