MTRR_RAT
ID MTRR_RAT Reviewed; 700 AA.
AC Q498R1; D3ZDG8;
DT 31-MAY-2011, integrated into UniProtKB/Swiss-Prot.
DT 31-MAY-2011, sequence version 2.
DT 03-AUG-2022, entry version 114.
DE RecName: Full=Methionine synthase reductase;
DE Short=MSR;
DE EC=1.16.1.8 {ECO:0000250|UniProtKB:Q9UBK8};
DE AltName: Full=Aquacobalamin reductase;
DE Short=AqCbl reductase;
GN Name=Mtrr;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Thymus;
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).
CC -!- FUNCTION: Key enzyme in methionine and folate homeostasis responsible
CC for the reactivation of methionine synthase (MTR/MS) activity by
CC catalyzing the reductive methylation of MTR-bound cob(II)alamin.
CC Cobalamin (vitamin B12) forms a complex with MTR to serve as an
CC intermediary in methyl transfer reactions that cycles between MTR-bound
CC methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional
CC oxidative escape of the cob(I)alamin intermediate during the catalytic
CC cycle leads to the inactive cob(II)alamin species. The processing of
CC cobalamin in the cytosol occurs in a multiprotein complex composed of
CC at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle
CC safely and efficiently cobalamin towards MTR in order to produce
CC methionine (By similarity). Also necessary for the utilization of
CC methyl groups from the folate cycle, thereby affecting
CC transgenerational epigenetic inheritance (By similarity). Also acts as
CC a molecular chaperone for methionine synthase by stabilizing apoMTR and
CC incorporating methylcob(III)alamin into apoMTR to form the holoenzyme.
CC Also serves as an aquacob(III)alamin reductase by reducing
CC aquacob(III)alamin to cob(II)alamin; this reduction leads to
CC stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR
CC holoenzyme (By similarity). {ECO:0000250|UniProtKB:Q8C1A3,
CC ECO:0000250|UniProtKB:Q9UBK8}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + 2 methylcob(III)alamin-[methionine synthase] + NADP(+)
CC + 2 S-adenosyl-L-homocysteine = 2 cob(II)alamin-[methionine synthase]
CC + NADPH + 2 S-adenosyl-L-methionine; Xref=Rhea:RHEA:23908, Rhea:RHEA-
CC COMP:14714, Rhea:RHEA-COMP:14715, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16304, ChEBI:CHEBI:28115, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:58349, ChEBI:CHEBI:59789; EC=1.16.1.8;
CC Evidence={ECO:0000250|UniProtKB:Q9UBK8};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:23910;
CC Evidence={ECO:0000250|UniProtKB:Q9UBK8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=A + 2 cob(II)alamin + 2 H(+) + 2 H2O = AH2 + 2
CC aquacob(III)alamin; Xref=Rhea:RHEA:20752, ChEBI:CHEBI:13193,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15852,
CC ChEBI:CHEBI:16304, ChEBI:CHEBI:17499;
CC Evidence={ECO:0000250|UniProtKB:Q9UBK8};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:20754;
CC Evidence={ECO:0000250|UniProtKB:Q9UBK8};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:Q9UBK8};
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000250|UniProtKB:Q9UBK8};
CC -!- SUBUNIT: Forms a multiprotein complex with MMACHC, MMADHC AND MTR.
CC {ECO:0000250|UniProtKB:Q9UBK8}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9UBK8}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q498R1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q498R1-2; Sequence=VSP_041294;
CC -!- MISCELLANEOUS: It is debated whether the reduction of free
CC aquacob(II)alamin occurs spontaneously or is enzyme catalyzed.
CC {ECO:0000305}.
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DR EMBL; CH474002; EDL87600.1; -; Genomic_DNA.
DR EMBL; BC100107; AAI00108.1; -; mRNA.
DR RefSeq; NP_001034092.1; NM_001039003.1. [Q498R1-2]
DR RefSeq; XP_006227875.1; XM_006227813.3. [Q498R1-1]
DR AlphaFoldDB; Q498R1; -.
DR SMR; Q498R1; -.
DR STRING; 10116.ENSRNOP00000024041; -.
DR PaxDb; Q498R1; -.
DR Ensembl; ENSRNOT00000061790; ENSRNOP00000058505; ENSRNOG00000017826. [Q498R1-2]
DR Ensembl; ENSRNOT00000094903; ENSRNOP00000078665; ENSRNOG00000017826. [Q498R1-1]
DR GeneID; 290947; -.
DR KEGG; rno:290947; -.
DR UCSC; RGD:1308671; rat. [Q498R1-1]
DR CTD; 4552; -.
DR RGD; 1308671; Mtrr.
DR eggNOG; KOG1158; Eukaryota.
DR GeneTree; ENSGT00940000155822; -.
DR HOGENOM; CLU_001570_17_0_1; -.
DR InParanoid; Q498R1; -.
DR OMA; TDRREHC; -.
DR OrthoDB; 318396at2759; -.
DR TreeFam; TF105716; -.
DR Reactome; R-RNO-156581; Methylation.
DR Reactome; R-RNO-1614635; Sulfur amino acid metabolism.
DR Reactome; R-RNO-9759218; Cobalamin (Cbl) metabolism.
DR PRO; PR:Q498R1; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Proteomes; UP000234681; Chromosome 1.
DR Bgee; ENSRNOG00000017826; Expressed in quadriceps femoris and 19 other tissues.
DR Genevisible; Q498R1; RN.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0045111; C:intermediate filament cytoskeleton; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0030586; F:[methionine synthase] reductase activity; ISO:RGD.
DR GO; GO:0071949; F:FAD binding; ISO:RGD.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISS:UniProtKB.
DR GO; GO:0010181; F:FMN binding; ISO:RGD.
DR GO; GO:0070402; F:NADPH binding; ISO:RGD.
DR GO; GO:0003958; F:NADPH-hemoprotein reductase activity; ISO:RGD.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0016723; F:oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor; ISS:UniProtKB.
DR GO; GO:0009235; P:cobalamin metabolic process; ISO:RGD.
DR GO; GO:0006306; P:DNA methylation; ISS:UniProtKB.
DR GO; GO:0046655; P:folic acid metabolic process; ISS:UniProtKB.
DR GO; GO:0043418; P:homocysteine catabolic process; ISO:RGD.
DR GO; GO:0050667; P:homocysteine metabolic process; ISO:RGD.
DR GO; GO:0009086; P:methionine biosynthetic process; ISO:RGD.
DR GO; GO:1904042; P:negative regulation of cystathionine beta-synthase activity; ISO:RGD.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:UniProt.
DR GO; GO:0033353; P:S-adenosylmethionine cycle; ISO:RGD.
DR Gene3D; 1.20.990.10; -; 1.
DR Gene3D; 3.40.50.360; -; 1.
DR Gene3D; 3.40.50.80; -; 1.
DR InterPro; IPR003097; CysJ-like_FAD-binding.
DR InterPro; IPR017927; FAD-bd_FR_type.
DR InterPro; IPR001094; Flavdoxin-like.
DR InterPro; IPR008254; Flavodoxin/NO_synth.
DR InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase.
DR InterPro; IPR029039; Flavoprotein-like_sf.
DR InterPro; IPR039261; FNR_nucleotide-bd.
DR InterPro; IPR023173; NADPH_Cyt_P450_Rdtase_alpha.
DR InterPro; IPR001433; OxRdtase_FAD/NAD-bd.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR Pfam; PF00667; FAD_binding_1; 1.
DR Pfam; PF00258; Flavodoxin_1; 1.
DR Pfam; PF00175; NAD_binding_1; 1.
DR PRINTS; PR00369; FLAVODOXIN.
DR PRINTS; PR00371; FPNCR.
DR SUPFAM; SSF52218; SSF52218; 1.
DR SUPFAM; SSF52343; SSF52343; 1.
DR SUPFAM; SSF63380; SSF63380; 1.
DR PROSITE; PS51384; FAD_FR; 1.
DR PROSITE; PS50902; FLAVODOXIN_LIKE; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Amino-acid biosynthesis; Cytoplasm; FAD;
KW Flavoprotein; FMN; Methionine biosynthesis; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome; S-adenosyl-L-methionine.
FT CHAIN 1..700
FT /note="Methionine synthase reductase"
FT /id="PRO_0000409309"
FT DOMAIN 4..147
FT /note="Flavodoxin-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00088"
FT DOMAIN 272..534
FT /note="FAD-binding FR-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00716"
FT REGION 168..247
FT /note="Hinge"
FT /evidence="ECO:0000250"
FT BINDING 10..14
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00088"
FT BINDING 93..124
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00088"
FT BINDING 292
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 452..455
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 488..491
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 611..612
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 626..628
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 661
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 699
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT MOD_RES 173
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UBK8"
FT MOD_RES 190
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UBK8"
FT VAR_SEQ 44..237
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_041294"
SQ SEQUENCE 700 AA; 78025 MW; 13EAE5AE46606F11 CRC64;
MRRFLLLYAT QRGQAKAIAE EISEQALSHG FSADLHCVSE SEKYDLKTET GPLVMVVSTT
GTGDPPDTAR KFVKEIHNKT LPTDFFAHLW YGLLGLGDSE YTYFCNGGKV IDKRLQELGA
QHFYDTGHAD DCVGLELVVE PWIDGLWPAL TKHFKSLGGQ EDMSDSDTLA QASDAPLSMA
MKPELLHIQS QVELLSLEDV GKRDSELQEQ NETNKNQPSR IEDFDSSLVN SVPPLSQSSL
SIPAVSPEYL EVYLQESLGQ DENQASVPPS VDPIFQVPIS KAVELTTNDA IKTTLLLELD
ISKVEFSHQP GDSFNVICPN SGSEVEDLLQ RLQLADKQAH RVILKIKMDT KKKGASLPQH
VPEGSSLQFI FTWCLEIRAV PKKAFLRALS DYTSDATEKR RLQELCSKQG AADYNRFIRD
ASVCLLDLLL TFPSCQPPLN LLLEHLPKLQ PRPYSCASSS LLHPDKLHFV FNIVELPSNT
TAASLRKGVC TGWLATLVAP FLQPNTEVLT ADHSDALAPE ILISPRATNS FHLPDDLSAP
IIMVGPGTGV APFVGFLQHR EKLQEQHPDG NFGAMWLFFG CRHKDRDYLF REELRHFLKT
GVLTHLKVSF SRDAAPEEEE EAPAKYVQDN LQHHSQQVAR TLLQENGYIY VCGDAKNMAK
DVHDALVEII SKEAGVDKLE AMKTLATLKQ EKRYLQDIWS
