MTHR_MOUSE
ID MTHR_MOUSE Reviewed; 654 AA.
AC Q9WU20; Q8CDE4;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=Methylenetetrahydrofolate reductase {ECO:0000305};
DE EC=1.5.1.20 {ECO:0000250|UniProtKB:P42898};
GN Name=Mthfr {ECO:0000312|MGI:MGI:106639};
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 [GENOMIC DNA].
RX PubMed=9680386; DOI=10.1007/s003359900838;
RA Goyette P., Pai A., Milos R., Frosst P., Tran P., Chen Z., Chan M.,
RA Rozen R.;
RT "Gene structure of human and mouse methylenetetrahydrofolate reductase
RT (MTHFR).";
RL Mamm. Genome 9:652-656(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Testis;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain, and Olfactory epithelium;
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 [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Lung, and Testis;
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).
CC -!- FUNCTION: Catalyzes the conversion of 5,10-methylenetetrahydrofolate to
CC 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation
CC to methionine. Represents a key regulatory connection between the
CC folate and methionine cycles. {ECO:0000250|UniProtKB:P42898}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)-5,10-
CC methylene-5,6,7,8-tetrahydrofolate + H(+) + NADPH;
CC Xref=Rhea:RHEA:19817, ChEBI:CHEBI:15378, ChEBI:CHEBI:15636,
CC ChEBI:CHEBI:18608, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.5.1.20;
CC Evidence={ECO:0000250|UniProtKB:P42898};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19819;
CC Evidence={ECO:0000250|UniProtKB:P42898};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + NAD(+) = (6R)-5,10-
CC methylene-5,6,7,8-tetrahydrofolate + H(+) + NADH;
CC Xref=Rhea:RHEA:19821, ChEBI:CHEBI:15378, ChEBI:CHEBI:15636,
CC ChEBI:CHEBI:18608, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.5.1.20;
CC Evidence={ECO:0000250|UniProtKB:P42898};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19823;
CC Evidence={ECO:0000250|UniProtKB:P42898};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:P42898};
CC -!- ACTIVITY REGULATION: Allosterically regulated by S-adenosylmethionine
CC (SAM). {ECO:0000250|UniProtKB:P42898}.
CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC {ECO:0000250|UniProtKB:P42898}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P42898}.
CC -!- DOMAIN: Contains a serine-rich phosphorylation region at the N-terminal
CC and an eukaryote-only S-adenosylmethionine (SAM)-binding domain at the
CC C-terminal. Through asymmetric homodimerization, the two regions are
CC positioned next to each other and N-terminal phosphorylation increases
CC sensitivity to SAM binding and inhibition.
CC {ECO:0000250|UniProtKB:P42898}.
CC -!- PTM: Phosphorylation of an N-terminal serine-rich phosphorylation
CC region increases sensitivity to S-adenosylmethionine and inhibition.
CC {ECO:0000250|UniProtKB:P42898}.
CC -!- SIMILARITY: Belongs to the methylenetetrahydrofolate reductase family.
CC {ECO:0000305}.
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DR EMBL; AF105998; AAD20313.1; -; Genomic_DNA.
DR EMBL; AF105988; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105989; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105990; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105991; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105992; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105993; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105994; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105995; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105996; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AF105997; AAD20313.1; JOINED; Genomic_DNA.
DR EMBL; AK030192; BAC26832.1; -; mRNA.
DR EMBL; AL606929; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466594; EDL14794.1; -; Genomic_DNA.
DR EMBL; CH466594; EDL14796.1; -; Genomic_DNA.
DR EMBL; CH466594; EDL14797.1; -; Genomic_DNA.
DR EMBL; BC051017; AAH51017.1; -; mRNA.
DR EMBL; BC052466; AAH52466.1; -; mRNA.
DR CCDS; CCDS18929.1; -.
DR RefSeq; NP_034970.2; NM_010840.3.
DR AlphaFoldDB; Q9WU20; -.
DR SMR; Q9WU20; -.
DR STRING; 10090.ENSMUSP00000069774; -.
DR iPTMnet; Q9WU20; -.
DR PhosphoSitePlus; Q9WU20; -.
DR EPD; Q9WU20; -.
DR MaxQB; Q9WU20; -.
DR PaxDb; Q9WU20; -.
DR PRIDE; Q9WU20; -.
DR ProteomicsDB; 291452; -.
DR Antibodypedia; 28242; 415 antibodies from 38 providers.
DR DNASU; 17769; -.
DR Ensembl; ENSMUST00000097788; ENSMUSP00000095395; ENSMUSG00000029009.
DR GeneID; 17769; -.
DR KEGG; mmu:17769; -.
DR UCSC; uc008vtu.2; mouse.
DR CTD; 4524; -.
DR MGI; MGI:106639; Mthfr.
DR VEuPathDB; HostDB:ENSMUSG00000029009; -.
DR eggNOG; KOG0564; Eukaryota.
DR GeneTree; ENSGT00390000012490; -.
DR HOGENOM; CLU_025841_2_0_1; -.
DR InParanoid; Q9WU20; -.
DR OrthoDB; 338303at2759; -.
DR BRENDA; 1.5.1.15; 3474.
DR BRENDA; 1.5.1.20; 3474.
DR Reactome; R-MMU-196757; Metabolism of folate and pterines.
DR UniPathway; UPA00193; -.
DR BioGRID-ORCS; 17769; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Mthfr; mouse.
DR PRO; PR:Q9WU20; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; Q9WU20; protein.
DR Bgee; ENSMUSG00000029009; Expressed in saccule of membranous labyrinth and 251 other tissues.
DR ExpressionAtlas; Q9WU20; baseline and differential.
DR Genevisible; Q9WU20; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0045202; C:synapse; ISO:MGI.
DR GO; GO:0071949; F:FAD binding; IBA:GO_Central.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISO:MGI.
DR GO; GO:0004489; F:methylenetetrahydrofolate reductase (NAD(P)H) activity; IMP:MGI.
DR GO; GO:0106312; F:methylenetetrahydrofolate reductase NADH activity; IEA:RHEA.
DR GO; GO:0106313; F:methylenetetrahydrofolate reductase NADPH activity; IEA:RHEA.
DR GO; GO:0072341; F:modified amino acid binding; ISO:MGI.
DR GO; GO:0050661; F:NADP binding; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0070828; P:heterochromatin organization; ISO:MGI.
DR GO; GO:0050667; P:homocysteine metabolic process; ISO:MGI.
DR GO; GO:0009086; P:methionine biosynthetic process; IMP:MGI.
DR GO; GO:0006555; P:methionine metabolic process; ISO:MGI.
DR GO; GO:0001843; P:neural tube closure; ISO:MGI.
DR GO; GO:0031060; P:regulation of histone methylation; ISO:MGI.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; ISS:UniProtKB.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; ISO:MGI.
DR CDD; cd00537; MTHFR; 1.
DR InterPro; IPR029041; FAD-linked_oxidoreductase-like.
DR InterPro; IPR004621; Fadh2_euk.
DR InterPro; IPR003171; Mehydrof_redctse-like.
DR Pfam; PF02219; MTHFR; 1.
DR SUPFAM; SSF51730; SSF51730; 1.
DR TIGRFAMs; TIGR00677; fadh2_euk; 1.
PE 1: Evidence at protein level;
KW Allosteric enzyme; FAD; Flavoprotein; NADP; Oxidoreductase; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..654
FT /note="Methylenetetrahydrofolate reductase"
FT /id="PRO_0000190247"
FT REGION 1..41
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..32
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 62
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT BINDING 62..67
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 93..94
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 93..94
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 126
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 156..158
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 158
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 173..174
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 196
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 200..203
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 209
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 216
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 227
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 320
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 324
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 455
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 460..463
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 480..484
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 559
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 572
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 18
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 19
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 20
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 22
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 24
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 25
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 28
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 29
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 33
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 93
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 102
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 393
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 450
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT CONFLICT 303
FT /note="S -> R (in Ref. 1; AAD20313)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 654 AA; 74580 MW; 96E625014D8F4838 CRC64;
MVNEARGSGS PNPRSEGSSS GSESSKDSSR CSTPSLDPER HERLREKMRR RMDSGDKWFS
LEFFPPRTAE GAVNLISRFD RMAAGGPLFV DVTWHPAGDP GSDKETSSMM IASTAVNYCG
LETILHMTCC QQRPEEITGH LHRAKQLGLK NIMALRGDPV GDHWEAEEGG FSYATDLVKH
IRTEFADYFD ICVAGYPRGH PDAESFEDDL KHLKEKVSAG ADFIITQLFF EASTFFSFVK
ACTEIGISCP ILPGIFPIQG YTSLRQLVKL SKLEVPQKIK DVIEPIKDND AAIRNYGIEL
AVSLCRELLD SGLVPGLHFY TLNREVATME VLKQLGMWTE DPRRPLPWAL SAHPKRREED
VRPIFWASRP KSYIYRTQDW DEFPNGRWGN SSSPAFGELK DYYLFYLKSK SPREELLKMW
GEELTSEESV FEVFEHYLSG EPNRHGYRVT CLPWNDEPLA AETSLMKEEL LRVNRLGILT
INSQPNINAK PSSDPVVGWG PSGGYVFQKA YLEFFTSRET VEALLQVLKT YELRVNYHIV
DVKGENITNA PELQPNAVTW GIFPGREIIQ PTVVDPISFM FWKDEAFALW IEQWGKLYEE
ESPSRMIIQY IHDNYFLVNL VDNEFPLDSC LWQVVEDTFE LLNRHPTERE TQAP
