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   27-MAR-2024, entry version 128.
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; 10090-ENSMUSP00000030453; -.
DR   ProteomicsDB; 291469; -.
DR   Pumba; Q9CZD0; -.
DR   ABCD; Q9CZD0; 1 sequenced antibody.
DR   Antibodypedia; 32641; 449 antibodies from 31 providers.
DR   DNASU; 67096; -.
DR   Ensembl; ENSMUST00000030453.5; ENSMUSP00000030453.5; ENSMUSG00000028690.5.
DR   GeneID; 67096; -.
DR   KEGG; mmu:67096; -.
DR   UCSC; uc008uhe.1; mouse.
DR   AGR; MGI:1914346; -.
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; SDPVDQC; -.
DR   OrthoDB; 3035512at2759; -.
DR   PhylomeDB; Q9CZD0; -.
DR   TreeFam; TF332476; -.
DR   Reactome; R-MMU-9759218; Cobalamin (Cbl) metabolism.
DR   BioGRID-ORCS; 67096; 18 hits in 76 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 252 other cell types or tissues.
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:SF2; CYANOCOBALAMIN REDUCTASE _ ALKYLCOBALAMIN DEALKYLASE; 1.
DR   PANTHER; PTHR31457; METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA TYPE C PROTEIN; 1.
DR   Pfam; PF16690; MMACHC; 1.
DR   Genevisible; Q9CZD0; MM.
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
//