MTRR_MOUSE
ID MTRR_MOUSE Reviewed; 696 AA.
AC Q8C1A3; Q3U2C6; Q8R0Y3;
DT 31-MAY-2011, integrated into UniProtKB/Swiss-Prot.
DT 31-MAY-2011, sequence version 2.
DT 03-AUG-2022, entry version 145.
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 {ECO:0000312|MGI:MGI:1891037};
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, and NOD; TISSUE=Corpora quadrigemina, and Skin;
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 GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Liver;
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 [4]
RP DISRUPTION PHENOTYPE.
RX PubMed=18413293; DOI=10.1016/j.ymgme.2008.03.004;
RA Deng L., Elmore C.L., Lawrance A.K., Matthews R.G., Rozen R.;
RT "Methionine synthase reductase deficiency results in adverse reproductive
RT outcomes and congenital heart defects in mice.";
RL Mol. Genet. Metab. 94:336-342(2008).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, and Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24074862; DOI=10.1016/j.cell.2013.09.002;
RA Padmanabhan N., Jia D., Geary-Joo C., Wu X., Ferguson-Smith A.C., Fung E.,
RA Bieda M.C., Snyder F.F., Gravel R.A., Cross J.C., Watson E.D.;
RT "Mutation in folate metabolism causes epigenetic instability and
RT transgenerational effects on development.";
RL Cell 155:81-93(2013).
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 (PubMed:24074862). Also acts
CC as a molecular chaperone for methionine synthase by stabilizing apoMTR
CC and incorporating methylcob(III)alamin into apoMTR to form the
CC holoenzyme. 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:Q9UBK8,
CC ECO:0000269|PubMed:24074862}.
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 -!- 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 -!- DISRUPTION PHENOTYPE: Female mice have more resorptions and more
CC delayed embryos per litter as well as embryonic delays and defects:
CC placentae of mothers are smaller and their embryos are smaller and
CC display myocardial hypoplasia and a higher incidence of ventricular
CC septal defects per litter (PubMed:18413293). Epigenetic transmission of
CC developmental disorders between generations: a hypomorphic mutation
CC disrupts folate metabolism and is associated with effects on offspring
CC development that are transmitted transgenerationally. The epigenetic
CC influences caused by Mtrr hypomorphic deficiency in mice leads to 2
CC distinctive phenotypes: (1) an atypical uterine environment in their
CC wild-type daughters that causes growth defects in their wild-type
CC grandprogeny and (2) congenital malformations in their wild-type
CC grandprogeny due to epigenetic inheritance via the germline, the
CC effects of which persist for at least up to 4 wild-type generations
CC after an Mtrr-deficient maternal ancestor. These effects are associated
CC with altered DNA methylation patterns (PubMed:24074862).
CC {ECO:0000269|PubMed:18413293, ECO:0000269|PubMed:24074862}.
CC -!- MISCELLANEOUS: It is debated whether the reduction of free
CC aquacob(II)alamin occurs spontaneously or is enzyme catalyzed.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The hidden things - Issue
CC 166 of December 2014;
CC URL="https://web.expasy.org/spotlight/back_issues/166/";
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DR EMBL; AK028628; BAC26039.1; -; mRNA.
DR EMBL; AK155359; BAE33215.1; -; mRNA.
DR EMBL; AK163449; BAE37348.1; -; mRNA.
DR EMBL; CH466563; EDL37004.1; -; Genomic_DNA.
DR EMBL; BC025942; AAH25942.1; -; mRNA.
DR CCDS; CCDS26620.1; -.
DR RefSeq; NP_001295404.1; NM_001308475.1.
DR RefSeq; NP_766068.1; NM_172480.3.
DR RefSeq; XP_006517242.1; XM_006517179.3.
DR RefSeq; XP_006517244.1; XM_006517181.3.
DR RefSeq; XP_006517245.1; XM_006517182.1.
DR AlphaFoldDB; Q8C1A3; -.
DR SMR; Q8C1A3; -.
DR BioGRID; 229121; 1.
DR STRING; 10090.ENSMUSP00000039810; -.
DR iPTMnet; Q8C1A3; -.
DR PhosphoSitePlus; Q8C1A3; -.
DR EPD; Q8C1A3; -.
DR MaxQB; Q8C1A3; -.
DR PaxDb; Q8C1A3; -.
DR PeptideAtlas; Q8C1A3; -.
DR PRIDE; Q8C1A3; -.
DR ProteomicsDB; 287329; -.
DR DNASU; 210009; -.
DR GeneID; 210009; -.
DR KEGG; mmu:210009; -.
DR UCSC; uc007rby.1; mouse.
DR CTD; 4552; -.
DR MGI; MGI:1891037; Mtrr.
DR eggNOG; KOG1158; Eukaryota.
DR InParanoid; Q8C1A3; -.
DR OrthoDB; 318396at2759; -.
DR TreeFam; TF105716; -.
DR Reactome; R-MMU-156581; Methylation.
DR Reactome; R-MMU-1614635; Sulfur amino acid metabolism.
DR Reactome; R-MMU-9759218; Cobalamin (Cbl) metabolism.
DR BioGRID-ORCS; 210009; 16 hits in 73 CRISPR screens.
DR ChiTaRS; Mtrr; mouse.
DR PRO; PR:Q8C1A3; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q8C1A3; protein.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0045111; C:intermediate filament cytoskeleton; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0030586; F:[methionine synthase] reductase activity; IMP:BHF-UCL.
DR GO; GO:0071949; F:FAD binding; ISO:MGI.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISS:UniProtKB.
DR GO; GO:0010181; F:FMN binding; ISO:MGI.
DR GO; GO:0070402; F:NADPH binding; ISO:MGI.
DR GO; GO:0003958; F:NADPH-hemoprotein reductase activity; ISO:MGI.
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; IMP:MGI.
DR GO; GO:0006306; P:DNA methylation; IMP:UniProtKB.
DR GO; GO:0046655; P:folic acid metabolic process; IMP:UniProtKB.
DR GO; GO:0043418; P:homocysteine catabolic process; ISO:MGI.
DR GO; GO:0050667; P:homocysteine metabolic process; IMP:BHF-UCL.
DR GO; GO:0009086; P:methionine biosynthetic process; IMP:BHF-UCL.
DR GO; GO:1904042; P:negative regulation of cystathionine beta-synthase activity; ISO:MGI.
DR GO; GO:0050821; P:protein stabilization; ISO:MGI.
DR GO; GO:0033353; P:S-adenosylmethionine cycle; IMP:BHF-UCL.
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 1: Evidence at protein level;
KW Amino-acid biosynthesis; Cytoplasm; FAD; Flavoprotein; FMN;
KW Methionine biosynthesis; NADP; Oxidoreductase; Phosphoprotein;
KW Reference proteome; S-adenosyl-L-methionine.
FT CHAIN 1..696
FT /note="Methionine synthase reductase"
FT /id="PRO_0000409308"
FT DOMAIN 4..147
FT /note="Flavodoxin-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00088"
FT DOMAIN 269..531
FT /note="FAD-binding FR-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00716"
FT REGION 166..245
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 289
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 449..452
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 485..488
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 608..609
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 622..624
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 657
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 695
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT MOD_RES 171
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UBK8"
FT MOD_RES 188
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CONFLICT 90
FT /note="R -> Q (in Ref. 1; BAC26039/BAE37348)"
FT /evidence="ECO:0000305"
FT CONFLICT 190
FT /note="V -> F (in Ref. 3; AAH25942)"
FT /evidence="ECO:0000305"
FT CONFLICT 198
FT /note="V -> M (in Ref. 1; BAC26039/BAE37348)"
FT /evidence="ECO:0000305"
FT CONFLICT 482
FT /note="P -> L (in Ref. 1; BAC26039/BAE37348)"
FT /evidence="ECO:0000305"
FT CONFLICT 508
FT /note="A -> V (in Ref. 1; BAC26039/BAE37348)"
FT /evidence="ECO:0000305"
FT CONFLICT 513
FT /note="T -> A (in Ref. 1; BAC26039/BAE37348)"
FT /evidence="ECO:0000305"
FT CONFLICT 645
FT /note="I -> V (in Ref. 1; BAC26039/BAE37348)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 696 AA; 77518 MW; 740E3A5D9440FC81 CRC64;
MRRFLLLYAT QRGQAKAIAE EISEQAVSHG FSADLHCISE SEKYDLKTET GPLVMVVSTT
GTGDPPDTAR KFVKEIHNKT LPTDYFAHLR YGLLGLGDSE YTYFCNGGKV IDKRLQELGA
QRFYDTGHAD DCVGLELVVE PWIDGLWAAL TKHFKSLGGQ ENMSDTLSRA SDAPLSTAMK
PELLHIQSQV ELLRLEDVGE RDSELREQNE TNRGQQGRIE DFDSSLVHSV PPLSQSSLSI
PAVPPEYLEV HLQESLGQEE NQASVPSGDP SFQVPISKAI RLTTNDAVKS TLLLELDISK
IEFSHQPGDS FNVTCPNSDR EVEELLQRLQ LADKRAHRVI LKIKTDTKKK GAALPAHVPE
GRSLQFILTW CLEIRAVPKK AFLRALAEHT SSATEKRRLQ ELCSKQGAAD YNRFIRDASV
CLLDLLLTFP SCQPPLSLLL EHLPKLQPRP YSCASSSLRH PDKLHFVFNI VEFPPSTTAA
SPRKGVCTGW LATLVAPFLQ PNTDVSNADS GDTLAPEIRI SPRATNAFHL PEDPSAPIIM
VGPGTGVAPF VGFLQHREKL QEQHPDGKFG AMWLFFGCRH KDRDYLFREE LRHFLKTGVL
THLKVSFSRD AAPDGEEAPA KYVQDNLQRH SQQVARTLLQ ENGYIYVCGD AKNMAKDVND
TLIGIISNEA GVDKLEAMKT LATLKQEKRY LQDIWS
