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 03-AUG-2022, entry version 81.
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; Q5RFU5; -.
DR PRIDE; Q5RFU5; -.
DR GeneID; 555267; -.
DR KEGG; dre:555267; -.
DR CTD; 25974; -.
DR ZFIN; ZDB-GENE-030131-3167; mmachc.
DR eggNOG; KOG4552; Eukaryota.
DR InParanoid; Q5RFU5; -.
DR OrthoDB; 1375709at2759; -.
DR PhylomeDB; Q5RFU5; -.
DR Reactome; R-DRE-9759218; Cobalamin (Cbl) metabolism.
DR PRO; PR:Q5RFU5; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Unplaced.
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; PTHR31457; 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
