METH_MOUSE
ID METH_MOUSE Reviewed; 1253 AA.
AC A6H5Y3; Q3UQP2;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 24-JUL-2007, sequence version 1.
DT 03-AUG-2022, entry version 123.
DE RecName: Full=Methionine synthase;
DE Short=MS;
DE EC=2.1.1.13 {ECO:0000250|UniProtKB:Q9Z2Q4};
DE AltName: Full=5-methyltetrahydrofolate--homocysteine methyltransferase;
DE AltName: Full=Cobalamin-dependent methionine synthase;
DE AltName: Full=Vitamin-B12 dependent methionine synthase;
GN Name=Mtr {ECO:0000312|MGI:MGI:894292};
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 TISSUE=Brain;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-738.
RC STRAIN=C57BL/6J; TISSUE=Heart;
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Kidney, Lung, Pancreas, Spleen, 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 transfer of a methyl group from
CC methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound
CC cob(I)alamin and methionine in the cytosol. MeCbl is an active form of
CC cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis.
CC Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl
CC group from 5-methyltetrahydrofolate. The processing of cobalamin in the
CC cytosol occurs in a multiprotein complex composed of at least MMACHC,
CC MMADHC, MTRR (methionine synthase reductase) and MTR which may
CC contribute to shuttle safely and efficiently cobalamin towards MTR in
CC order to produce methionine. {ECO:0000250|UniProtKB:Q99707}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + L-homocysteine =
CC (6S)-5,6,7,8-tetrahydrofolate + L-methionine; Xref=Rhea:RHEA:11172,
CC ChEBI:CHEBI:18608, ChEBI:CHEBI:57453, ChEBI:CHEBI:57844,
CC ChEBI:CHEBI:58199; EC=2.1.1.13;
CC Evidence={ECO:0000250|UniProtKB:Q9Z2Q4};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11173;
CC Evidence={ECO:0000250|UniProtKB:Q9Z2Q4};
CC -!- COFACTOR:
CC Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115;
CC Evidence={ECO:0000250|UniProtKB:P13009};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P13009};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:P13009};
CC -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via de novo
CC pathway; L-methionine from L-homocysteine (MetH route): step 1/1.
CC {ECO:0000250|UniProtKB:Q9Z2Q4}.
CC -!- SUBUNIT: Monomer. Dimer. Forms a multiprotein complex with MMACHC,
CC MMADHC AND MTRR. {ECO:0000250|UniProtKB:Q99707}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q99707}.
CC -!- DOMAIN: Modular enzyme with four functionally distinct domains. The
CC isolated Hcy-binding domain catalyzes methyl transfer from free
CC methylcobalamin to homocysteine. The Hcy-binding domain in association
CC with the pterin-binding domain catalyzes the methylation of
CC cob(I)alamin by methyltetrahydrofolate and the methylation of
CC homocysteine. The B12-binding domain binds the cofactor. The AdoMet
CC activation domain binds S-adenosyl-L-methionine. Under aerobic
CC conditions cob(I)alamin can be converted to inactive cob(II)alamin.
CC Reductive methylation by S-adenosyl-L-methionine and flavodoxin
CC regenerates methylcobalamin (By similarity).
CC {ECO:0000250|UniProtKB:P13009}.
CC -!- SIMILARITY: Belongs to the vitamin-B12 dependent methionine synthase
CC family. {ECO:0000305}.
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DR EMBL; BC145683; AAI45684.1; -; mRNA.
DR EMBL; BC145685; AAI45686.1; -; mRNA.
DR EMBL; AK142258; BAE24997.1; -; mRNA.
DR CCDS; CCDS36591.1; -.
DR RefSeq; NP_001074597.1; NM_001081128.3.
DR AlphaFoldDB; A6H5Y3; -.
DR SMR; A6H5Y3; -.
DR BioGRID; 231991; 4.
DR IntAct; A6H5Y3; 1.
DR MINT; A6H5Y3; -.
DR STRING; 10090.ENSMUSP00000097442; -.
DR ChEMBL; CHEMBL3188; -.
DR iPTMnet; A6H5Y3; -.
DR PhosphoSitePlus; A6H5Y3; -.
DR EPD; A6H5Y3; -.
DR MaxQB; A6H5Y3; -.
DR PaxDb; A6H5Y3; -.
DR PeptideAtlas; A6H5Y3; -.
DR PRIDE; A6H5Y3; -.
DR ProteomicsDB; 252541; -.
DR Antibodypedia; 20817; 158 antibodies from 30 providers.
DR Ensembl; ENSMUST00000099856; ENSMUSP00000097442; ENSMUSG00000021311.
DR GeneID; 238505; -.
DR KEGG; mmu:238505; -.
DR UCSC; uc007plh.2; mouse.
DR CTD; 4548; -.
DR MGI; MGI:894292; Mtr.
DR VEuPathDB; HostDB:ENSMUSG00000021311; -.
DR eggNOG; KOG1579; Eukaryota.
DR GeneTree; ENSGT00420000029824; -.
DR HOGENOM; CLU_004914_2_0_1; -.
DR InParanoid; A6H5Y3; -.
DR OMA; ADCIAMS; -.
DR OrthoDB; 731388at2759; -.
DR PhylomeDB; A6H5Y3; -.
DR TreeFam; TF312829; -.
DR Reactome; R-MMU-156581; Methylation.
DR Reactome; R-MMU-1614635; Sulfur amino acid metabolism.
DR Reactome; R-MMU-9013407; RHOH GTPase cycle.
DR Reactome; R-MMU-9759218; Cobalamin (Cbl) metabolism.
DR UniPathway; UPA00051; UER00081.
DR BioGRID-ORCS; 238505; 17 hits in 74 CRISPR screens.
DR ChiTaRS; Mtr; mouse.
DR PRO; PR:A6H5Y3; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; A6H5Y3; protein.
DR Bgee; ENSMUSG00000021311; Expressed in myocardium of ventricle and 225 other tissues.
DR ExpressionAtlas; A6H5Y3; baseline and differential.
DR Genevisible; A6H5Y3; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0016597; F:amino acid binding; ISO:MGI.
DR GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-KW.
DR GO; GO:0005542; F:folic acid binding; ISO:MGI.
DR GO; GO:0008705; F:methionine synthase activity; IMP:MGI.
DR GO; GO:0008168; F:methyltransferase activity; ISO:MGI.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0031103; P:axon regeneration; ISO:MGI.
DR GO; GO:0071732; P:cellular response to nitric oxide; ISO:MGI.
DR GO; GO:0009235; P:cobalamin metabolic process; IMP: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:0006479; P:protein methylation; ISO:MGI.
DR GO; GO:0048678; P:response to axon injury; ISO:MGI.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; ISO:MGI.
DR CDD; cd02069; methionine_synthase_B12_BD; 1.
DR Gene3D; 1.10.1240.10; -; 1.
DR Gene3D; 3.10.196.10; -; 1.
DR Gene3D; 3.20.20.20; -; 1.
DR Gene3D; 3.20.20.330; -; 1.
DR InterPro; IPR003759; Cbl-bd_cap.
DR InterPro; IPR006158; Cobalamin-bd.
DR InterPro; IPR036724; Cobalamin-bd_sf.
DR InterPro; IPR011005; Dihydropteroate_synth-like.
DR InterPro; IPR003726; HCY_dom.
DR InterPro; IPR036589; HCY_dom_sf.
DR InterPro; IPR033706; Met_synthase_B12-bd.
DR InterPro; IPR011822; MetH.
DR InterPro; IPR036594; Meth_synthase_dom.
DR InterPro; IPR000489; Pterin-binding_dom.
DR InterPro; IPR004223; VitB12-dep_Met_synth_activ_dom.
DR InterPro; IPR037010; VitB12-dep_Met_synth_activ_sf.
DR Pfam; PF02310; B12-binding; 1.
DR Pfam; PF02607; B12-binding_2; 1.
DR Pfam; PF02965; Met_synt_B12; 1.
DR Pfam; PF00809; Pterin_bind; 1.
DR Pfam; PF02574; S-methyl_trans; 1.
DR PIRSF; PIRSF000381; MetH; 1.
DR SMART; SM01018; B12-binding_2; 1.
DR SUPFAM; SSF47644; SSF47644; 1.
DR SUPFAM; SSF51717; SSF51717; 1.
DR SUPFAM; SSF52242; SSF52242; 1.
DR SUPFAM; SSF56507; SSF56507; 1.
DR SUPFAM; SSF82282; SSF82282; 1.
DR TIGRFAMs; TIGR02082; metH; 1.
DR PROSITE; PS50974; ADOMET_ACTIVATION; 1.
DR PROSITE; PS51332; B12_BINDING; 1.
DR PROSITE; PS51337; B12_BINDING_NTER; 1.
DR PROSITE; PS50970; HCY; 1.
DR PROSITE; PS50972; PTERIN_BINDING; 1.
PE 1: Evidence at protein level;
KW Amino-acid biosynthesis; Cobalamin; Cobalt; Cytoplasm; Metal-binding;
KW Methionine biosynthesis; Methyltransferase; Phosphoprotein;
KW Reference proteome; Repeat; S-adenosyl-L-methionine; Transferase; Zinc.
FT CHAIN 1..1253
FT /note="Methionine synthase"
FT /id="PRO_0000312901"
FT DOMAIN 6..326
FT /note="Hcy-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT DOMAIN 359..620
FT /note="Pterin-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00334"
FT DOMAIN 650..747
FT /note="B12-binding N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00667"
FT DOMAIN 760..895
FT /note="B12-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00666"
FT DOMAIN 911..1253
FT /note="AdoMet activation"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00346"
FT BINDING 248
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT BINDING 311
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT BINDING 312
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT BINDING 370..372
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000250|UniProtKB:Q99707"
FT BINDING 437
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000250|UniProtKB:Q99707"
FT BINDING 458
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000250|UniProtKB:Q99707"
FT BINDING 525
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000250|UniProtKB:Q99707"
FT BINDING 567
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000250|UniProtKB:Q99707"
FT BINDING 573
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000250|UniProtKB:Q99707"
FT BINDING 579
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000250|UniProtKB:Q99707"
FT BINDING 697
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 770..774
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 773
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /ligand_part="Co"
FT /ligand_part_id="ChEBI:CHEBI:27638"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 818
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 822
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 874
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 962
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 1160
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 1215..1216
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT MOD_RES 1252
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2Q4"
FT CONFLICT 343
FT /note="M -> L (in Ref. 2; BAE24997)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1253 AA; 139069 MW; 5507CAD9F9522537 CRC64;
MKKTLQDEIE AILRKRIMVL DGGMGTMIQR YKLSEEHFQG QEFKDHSRPL KGNNDILSIT
QPDIIYQIHK EYLLAGADII ETNTFSSTSI AQADYGLEHL AYRMNKCSAD VARKAAEEIT
LQTGVKRFVA GALGPTNKTL SVSPSVERPD YRNITFDELV DAYQEQAKGL LDGRVDILLI
ETIFDTANAK AALFAIQNLF EENYAPPRPI FISGTIVDKS GRTLSGQTGE AFVTSVSHSD
PLCIGLNCSL GAAEMRPFIE TIGKCTTAYV LCYPNAGLPN TFGDYDETPS TMATHLKDFA
VDGLVNIVGG CCGSTPDHIR EIAEAVKKCK PRVPPASVFE GHMLLSGLEP FRIGPYTNFV
NIGERCNVAG SRKFAKLIMA GNYEEALSIA KAQVEMGAQV LDINMDDGML DGPSAMTRFC
NSIASEPDIA KVPLCIDSSN FAVIEAGLKC CQGKCIVNSI SLKEGEGDFL EKARKIKKFG
AAVVVMAFDE EGQATETDVK VNVCTRAYHL LVDKVGFNPN DIIFDPNILT IGTGMEEHNL
YAINFIHATR VIKETLPGVR ISGGLSNLSF SFRGMEAIRE AMHGVFLYHA IKFGMDMGIV
NAGNLPVYDA IHKDLLQLCE DLIWNKDSEA TEKLLRYAQT HGTGGKKVIQ TDEWRNGSIE
ERLEYALVKG IEKHIVEDTE EARLNGEKYP RPLNIIEGPL MNGMKVVGDL FGAGKMFLPQ
VIKSARVMKK AVGHLIPFME KEREEARLIN GSVEEEDPYQ GTIVLATVKG DVHDIGKNIV
GVVLACNNFR VIDLGVMTPC DKILQAALDH KADIIGLSGL ITPSLDEMIF VAKEMERLAI
KIPLLIGGAT TSRTHTAVKI APRYSAPVIH VLDASKSVVV CSQLLDENLR DDYFEEILEE
YEDIRQDHYE SLKERKYVPL SQARKHGFHI DWLSEPHPVK PTFIGTQVFE DYNLQKLVDY
IDWKPFFDVW QLRGKYPNRG FPKIFNDKAV GEEARKVYND AQNMLNILIS QKKLQARGVV
GFWPAQSVQD DIHLYAEGVV PQAAEPIATF YGLRQQAEKD SSSTDPYHCL SDFIAPLHSG
VCDYLGLFAV ACFGVEELSK TYEDDGDDYS SIMVKALGDR LAEAFAEELH ERVRRELWAY
SRSEQLGVPD LRRLRYEGIR PAPGYPSQPD HTEKLTMWRL ASIEQATGIR LTESLAMAPA
SAVSGLYFSN VKAKYFAVGK ISKDQTEDYA LRKNMPVAEV EKWLGPILGY DTD
