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   24-JAN-2024, entry version 152.
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.ENSMUSP00000152387; -.
DR   iPTMnet; Q8C1A3; -.
DR   PhosphoSitePlus; Q8C1A3; -.
DR   EPD; Q8C1A3; -.
DR   MaxQB; Q8C1A3; -.
DR   PaxDb; 10090-ENSMUSP00000039810; -.
DR   PeptideAtlas; Q8C1A3; -.
DR   ProteomicsDB; 287329; -.
DR   Pumba; Q8C1A3; -.
DR   DNASU; 210009; -.
DR   GeneID; 210009; -.
DR   KEGG; mmu:210009; -.
DR   UCSC; uc007rby.1; mouse.
DR   AGR; MGI:1891037; -.
DR   CTD; 4552; -.
DR   MGI; MGI:1891037; Mtrr.
DR   eggNOG; KOG1158; Eukaryota.
DR   InParanoid; Q8C1A3; -.
DR   OrthoDB; 276396at2759; -.
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 78 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: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:0050821; P:protein stabilization; ISO:MGI.
DR   GO; GO:0033353; P:S-adenosylmethionine cycle; IMP:BHF-UCL.
DR   CDD; cd06203; methionine_synthase_red; 1.
DR   Gene3D; 3.40.50.360; -; 1.
DR   Gene3D; 3.40.50.80; Nucleotide-binding domain of ferredoxin-NADP reductase (FNR) module; 1.
DR   Gene3D; 2.40.30.10; Translation factors; 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   PANTHER; PTHR19384:SF84; METHIONINE SYNTHASE REDUCTASE; 1.
DR   PANTHER; PTHR19384; NITRIC OXIDE SYNTHASE-RELATED; 1.
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; SSF52343; Ferredoxin reductase-like, C-terminal NADP-linked domain; 1.
DR   SUPFAM; SSF52218; Flavoproteins; 1.
DR   SUPFAM; SSF63380; Riboflavin synthase domain-like; 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
//