MMAC_BOVIN
ID MMAC_BOVIN Reviewed; 280 AA.
AC Q5E9C8;
DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 1.
DT 03-AUG-2022, entry version 82.
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;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=16305752; DOI=10.1186/1471-2164-6-166;
RA Harhay G.P., Sonstegard T.S., Keele J.W., Heaton M.P., Clawson M.L.,
RA Snelling W.M., Wiedmann R.T., Van Tassell C.P., Smith T.P.L.;
RT "Characterization of 954 bovine full-CDS cDNA sequences.";
RL BMC Genomics 6:166-166(2005).
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 -!- SIMILARITY: Belongs to the MMACHC family. {ECO:0000305}.
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DR EMBL; BT020992; AAX09009.1; -; mRNA.
DR AlphaFoldDB; Q5E9C8; -.
DR SMR; Q5E9C8; -.
DR STRING; 9913.ENSBTAP00000022638; -.
DR PaxDb; Q5E9C8; -.
DR Ensembl; ENSBTAT00000022638; ENSBTAP00000022638; ENSBTAG00000017027.
DR VEuPathDB; HostDB:ENSBTAG00000017027; -.
DR VGNC; VGNC:57129; MMACHC.
DR eggNOG; KOG4552; Eukaryota.
DR GeneTree; ENSGT00390000003464; -.
DR HOGENOM; CLU_095722_0_0_1; -.
DR InParanoid; Q5E9C8; -.
DR OMA; QMEVIAD; -.
DR TreeFam; TF332476; -.
DR BRENDA; 2.5.1.151; 908.
DR Reactome; R-BTA-9759218; Cobalamin (Cbl) metabolism.
DR Proteomes; UP000009136; Chromosome 3.
DR Bgee; ENSBTAG00000017027; Expressed in liver and 106 other tissues.
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; 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; IEA:Ensembl.
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 2: Evidence at transcript level;
KW Cobalamin; Cobalt; Cytoplasm; FAD; Flavoprotein; FMN; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..280
FT /note="Cyanocobalamin reductase / alkylcobalamin
FT dealkylase"
FT /id="PRO_0000076257"
FT REGION 256..280
FT /note="Disordered"
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 245
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT MOD_RES 247
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT MOD_RES 273
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
FT MOD_RES 277
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4U1"
SQ SEQUENCE 280 AA; 31633 MW; C6D44951116D5EBF CRC64;
MEPLVAELKQ KIEDTLCPFG FEVYPFQVAW YNALLPPAFH LPLPGPTLAF LVLSTPAMFD
QALKPFLQSH HLQPLTDPVD QCVAYHLGRV RESLPELQIE VIADYEVHPN RRPKILAQTA
AHVAGAAYYY QRQDVESDPW GTQHIAGVCI HPRFGGWFAI RGVVLLRGTE VPNLPPTKPV
DCVPTRADRI SLLERFNFHW RDWTYRDAVT PQERYSEEQK AYFSTPPAQR LALLGLLQPS
EEPSSPSQEL HITTLLSKKP QNPRRGWLSP TVSPPISPGP
