MMAC_MOUSE
ID MMAC_MOUSE Reviewed; 279 AA.
AC Q9CZD0; Q9D8S7;
DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 10-JAN-2006, sequence version 2.
DT 03-AUG-2022, entry version 119.
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 {ECO:0000312|MGI:MGI:1914346};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain, and Pancreas;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=21697092; DOI=10.1074/jbc.m111.261370;
RA Koutmos M., Gherasim C., Smith J.L., Banerjee R.;
RT "Structural basis of multifunctionality in a vitamin B12-processing
RT enzyme.";
RL J. Biol. Chem. 286:29780-29787(2011).
RN [4]
RP DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=24889031; DOI=10.1016/j.ymgme.2014.05.002;
RA Moreno-Garcia M.A., Pupavac M., Rosenblatt D.S., Tremblay M.L.,
RA Jerome-Majewska L.A.;
RT "The Mmachc gene is required for pre-implantation embryogenesis in the
RT mouse.";
RL Mol. Genet. Metab. 112:198-204(2014).
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 Interacts with LMBRD1 and ABCD4; the interaction ensures the transport
CC of cobalamin from the lysosome to the cytoplasm. Forms a multiprotein
CC complex with MMADHC, MTR and MTRR; the interaction with MTR could
CC modulate MMACHC-dependent processing of cobalamin. Heterodimer with
CC MMADHC; the interaction might play a role in the regulation of the
CC balance between AdoCbl and MeCbl synthesis.
CC {ECO:0000250|UniProtKB:Q9Y4U1}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9Y4U1}.
CC -!- TISSUE SPECIFICITY: Detected in liver and kidney (at protein level)
CC (PubMed:21697092). Detected in embryos (PubMed:24889031).
CC {ECO:0000269|PubMed:21697092, ECO:0000269|PubMed:24889031}.
CC -!- DISRUPTION PHENOTYPE: Complete embryonic lethality. All die before 3.5
CC dpc. {ECO:0000269|PubMed:24889031}.
CC -!- SIMILARITY: Belongs to the MMACHC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH54756.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAB25214.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAC39135.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AK007725; BAB25214.1; ALT_FRAME; mRNA.
DR EMBL; AK012761; BAB28451.1; -; mRNA.
DR EMBL; AK084194; BAC39135.1; ALT_INIT; mRNA.
DR EMBL; BC054756; AAH54756.1; ALT_INIT; mRNA.
DR CCDS; CCDS51278.1; -.
DR RefSeq; NP_080238.2; NM_025962.3.
DR AlphaFoldDB; Q9CZD0; -.
DR SMR; Q9CZD0; -.
DR CORUM; Q9CZD0; -.
DR STRING; 10090.ENSMUSP00000030453; -.
DR iPTMnet; Q9CZD0; -.
DR PhosphoSitePlus; Q9CZD0; -.
DR EPD; Q9CZD0; -.
DR PaxDb; Q9CZD0; -.
DR PRIDE; Q9CZD0; -.
DR ProteomicsDB; 291469; -.
DR ABCD; Q9CZD0; 1 sequenced antibody.
DR Antibodypedia; 32641; 404 antibodies from 31 providers.
DR DNASU; 67096; -.
DR Ensembl; ENSMUST00000030453; ENSMUSP00000030453; ENSMUSG00000028690.
DR GeneID; 67096; -.
DR KEGG; mmu:67096; -.
DR UCSC; uc008uhe.1; mouse.
DR CTD; 25974; -.
DR MGI; MGI:1914346; Mmachc.
DR VEuPathDB; HostDB:ENSMUSG00000028690; -.
DR eggNOG; KOG4552; Eukaryota.
DR GeneTree; ENSGT00390000003464; -.
DR HOGENOM; CLU_095722_0_0_1; -.
DR InParanoid; Q9CZD0; -.
DR OMA; QMEVIAD; -.
DR OrthoDB; 1375709at2759; -.
DR PhylomeDB; Q9CZD0; -.
DR TreeFam; TF332476; -.
DR Reactome; R-MMU-9759218; Cobalamin (Cbl) metabolism.
DR BioGRID-ORCS; 67096; 17 hits in 72 CRISPR screens.
DR ChiTaRS; Mmachc; mouse.
DR PRO; PR:Q9CZD0; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; Q9CZD0; protein.
DR Bgee; ENSMUSG00000028690; Expressed in myocardium of ventricle and 249 other tissues.
DR Genevisible; Q9CZD0; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-KW.
DR GO; GO:0033787; F:cyanocobalamin reductase (cyanide-eliminating) activity; ISS:UniProtKB.
DR GO; GO:0032451; F:demethylase activity; ISS:UniProtKB.
DR GO; GO:0071949; F:FAD binding; ISS:UniProtKB.
DR GO; GO:0043295; F:glutathione binding; ISS:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW.
DR GO; GO:0009235; P:cobalamin metabolic process; ISS:UniProtKB.
DR GO; GO:0070988; P:demethylation; ISS:UniProtKB.
DR GO; GO:0006749; P:glutathione metabolic process; ISS:UniProtKB.
DR CDD; cd12959; MMACHC-like; 1.
DR InterPro; IPR032037; MMACHC.
DR PANTHER; PTHR31457; PTHR31457; 1.
DR Pfam; PF16690; MMACHC; 1.
PE 1: Evidence at protein level;
KW Cobalamin; Cobalt; Cytoplasm; FAD; Flavoprotein; FMN; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..279
FT /note="Cyanocobalamin reductase / alkylcobalamin
FT dealkylase"
FT /id="PRO_0000076259"
FT REGION 239..279
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 239..271
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 104
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT BINDING 115..118
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT BINDING 129..131
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT BINDING 149
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT BINDING 160
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT MOD_RES 247
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT MOD_RES 272
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT MOD_RES 276
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT CONFLICT 14
FT /note="D -> G (in Ref. 1; BAB28451)"
FT /evidence="ECO:0000305"
FT CONFLICT 239
FT /note="P -> H (in Ref. 1; BAB28451)"
FT /evidence="ECO:0000305"
FT CONFLICT 256
FT /note="K -> T (in Ref. 1; BAB28451)"
FT /evidence="ECO:0000305"
FT CONFLICT 260
FT /note="S -> Y (in Ref. 1; BAB28451)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 279 AA; 31648 MW; 178FAEB388691B09 CRC64;
MEPRVAELKQ KIEDTLCPFG FEVYPFQVAW YNELLPPAFH LPFPGPTLAF LVLSTPAMFD
RALKPFLKSC HFQTLRDPVD QCVSYHLRSV TEKFPEVHME VIADYEVHPN RRPKILAQTA
AHVAGAAYYY QRQDVDADPW GTQHIAGVCI HPRFGGWFAI RGVMLLPGIE VPNLPPRKPP
DCVPTRAGRI TLLEGFNFHW RDWTYRDAVT PEERYSEEQK IYFSTPPAQR LALLGLAQPS
EHPSTTSELP LSLLTKPQNS RRARSWLSPS VSPPVSPGP
