ID G3V8A4_RAT Unreviewed; 1253 AA. AC G3V8A4; DT 16-NOV-2011, integrated into UniProtKB/TrEMBL. DT 16-NOV-2011, sequence version 1. DT 08-NOV-2023, entry version 87. DE RecName: Full=Methionine synthase {ECO:0000256|ARBA:ARBA00012032, ECO:0000256|PIRNR:PIRNR000381}; DE EC=2.1.1.13 {ECO:0000256|ARBA:ARBA00012032, ECO:0000256|PIRNR:PIRNR000381}; DE AltName: Full=5-methyltetrahydrofolate--homocysteine methyltransferase {ECO:0000256|PIRNR:PIRNR000381}; GN Name=Mtr {ECO:0000313|Ensembl:ENSRNOP00000023973.3, GN ECO:0000313|RGD:621283}; 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 {ECO:0000313|Ensembl:ENSRNOP00000023973.3, ECO:0000313|Proteomes:UP000002494}; RN [1] {ECO:0000313|Ensembl:ENSRNOP00000023973.3, ECO:0000313|Proteomes:UP000002494} RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=Brown Norway {ECO:0000313|Ensembl:ENSRNOP00000023973.3, RC ECO:0000313|Proteomes:UP000002494}; RX PubMed=15057822; DOI=10.1038/nature02426; RG Rat Genome Sequencing Project Consortium; RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J., RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G., RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G., RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G., RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S., RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T., RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D., RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L., RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D., RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M., RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C., RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J., RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H., RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X., RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q., RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P., RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A., RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C., RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J., RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J., RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F., RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A., RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A., RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J., RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E., RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M., RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C., RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L., RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W., RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y., RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V., RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M., RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S., RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B., RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R., RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J., RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D., RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S., RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S., RA Mockrin S., Collins F.S.; RT "Genome sequence of the Brown Norway rat yields insights into mammalian RT evolution."; RL Nature 428:493-521(2004). RN [2] {ECO:0007829|PubMed:22673903} RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22673903; RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., RA Olsen J.V.; RT "Quantitative maps of protein phosphorylation sites across 14 different rat RT organs and tissues."; RL Nat. Commun. 3:876-876(2012). RN [3] {ECO:0000313|Ensembl:ENSRNOP00000023973.3} RP IDENTIFICATION. RC STRAIN=Brown Norway {ECO:0000313|Ensembl:ENSRNOP00000023973.3}; RG Ensembl; RL Submitted (JUL-2023) to UniProtKB. 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:0000256|PIRNR:PIRNR000381}. 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:0000256|PIRNR:PIRNR000381}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000256|ARBA:ARBA00001947, CC ECO:0000256|PIRNR:PIRNR000381, ECO:0000256|PROSITE-ProRule:PRU00333}; CC -!- COFACTOR: CC Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115; CC Evidence={ECO:0000256|ARBA:ARBA00001956, CC ECO:0000256|PIRNR:PIRNR000381, ECO:0000256|PIRSR:PIRSR000381-1}; 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:0000256|ARBA:ARBA00005178, ECO:0000256|PIRNR:PIRNR000381}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000256|PIRNR:PIRNR000381}. 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. {ECO:0000256|PIRNR:PIRNR000381}. CC -!- SIMILARITY: Belongs to the vitamin-B12 dependent methionine synthase CC family. {ECO:0000256|ARBA:ARBA00010398}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR AlphaFoldDB; G3V8A4; -. DR SMR; G3V8A4; -. DR Ensembl; ENSRNOT00000023974.6; ENSRNOP00000023973.3; ENSRNOG00000017593.8. DR RGD; 621283; Mtr. DR GeneTree; ENSGT00420000029824; -. DR HOGENOM; CLU_004914_2_0_1; -. DR OMA; ADCIAMS; -. DR OrthoDB; 66796at2759; -. DR TreeFam; TF312829; -. DR UniPathway; UPA00051; UER00081. DR Proteomes; UP000002494; Chromosome 17. DR Bgee; ENSRNOG00000017593; Expressed in adult mammalian kidney and 18 other tissues. DR GO; GO:0005829; C:cytosol; IEA:Ensembl. DR GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-UniRule. DR GO; GO:0008705; F:methionine synthase activity; IDA:BHF-UCL. DR GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-UniRule. DR GO; GO:0031103; P:axon regeneration; IMP:BHF-UCL. DR GO; GO:0071732; P:cellular response to nitric oxide; IDA:BHF-UCL. DR GO; GO:0009235; P:cobalamin metabolic process; IEA:Ensembl. DR GO; GO:0006306; P:DNA methylation; IC:BHF-UCL. DR GO; GO:0042558; P:pteridine-containing compound metabolic process; IEA:InterPro. DR GO; GO:0048678; P:response to axon injury; IDA:BHF-UCL. DR CDD; cd02069; methionine_synthase_B12_BD; 1. DR CDD; cd00740; MeTr; 1. DR Gene3D; 3.40.50.280; Cobalamin-binding domain; 1. DR Gene3D; 1.10.288.10; Cobalamin-dependent Methionine Synthase, domain 2; 1. DR Gene3D; 3.20.20.20; Dihydropteroate synthase-like; 1. DR Gene3D; 3.20.20.330; Homocysteine-binding-like domain; 1. DR Gene3D; 1.10.1240.10; Methionine synthase domain; 1. DR Gene3D; 3.10.196.10; Vitamin B12-dependent methionine synthase, activation domain; 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 NCBIfam; TIGR02082; metH; 1. DR PANTHER; PTHR45833; METHIONINE SYNTHASE; 1. DR PANTHER; PTHR45833:SF1; METHIONINE SYNTHASE; 1. 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; SSF52242; Cobalamin (vitamin B12)-binding domain; 1. DR SUPFAM; SSF51717; Dihydropteroate synthetase-like; 1. DR SUPFAM; SSF82282; Homocysteine S-methyltransferase; 1. DR SUPFAM; SSF56507; Methionine synthase activation domain-like; 1. DR SUPFAM; SSF47644; Methionine synthase domain; 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 {ECO:0000256|ARBA:ARBA00022605, KW ECO:0000256|PIRNR:PIRNR000381}; KW Cobalamin {ECO:0000256|ARBA:ARBA00022628, ECO:0000256|PIRNR:PIRNR000381}; KW Cobalt {ECO:0000256|ARBA:ARBA00023285, ECO:0000256|PIRNR:PIRNR000381}; KW Cytoplasm {ECO:0000256|PIRNR:PIRNR000381}; KW Metal-binding {ECO:0000256|ARBA:ARBA00022723, KW ECO:0000256|PIRNR:PIRNR000381}; KW Methionine biosynthesis {ECO:0000256|ARBA:ARBA00023167, KW ECO:0000256|PIRNR:PIRNR000381}; KW Methyltransferase {ECO:0000256|ARBA:ARBA00022603, KW ECO:0000256|PIRNR:PIRNR000381}; KW Reference proteome {ECO:0000313|Proteomes:UP000002494}; KW Repeat {ECO:0000256|ARBA:ARBA00022737}; KW S-adenosyl-L-methionine {ECO:0000256|ARBA:ARBA00022691, KW ECO:0000256|PIRNR:PIRNR000381}; KW Transferase {ECO:0000256|ARBA:ARBA00022679, ECO:0000256|PIRNR:PIRNR000381}; KW Zinc {ECO:0000256|ARBA:ARBA00022833, ECO:0000256|PIRNR:PIRNR000381}. FT BINDING 248 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-1, FT ECO:0000256|PROSITE-ProRule:PRU00333" FT BINDING 311 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-1, FT ECO:0000256|PROSITE-ProRule:PRU00333" FT BINDING 312 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-1, FT ECO:0000256|PROSITE-ProRule:PRU00333" FT BINDING 697 FT /ligand="methylcob(III)alamin" FT /ligand_id="ChEBI:CHEBI:28115" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" FT BINDING 770..774 FT /ligand="methylcob(III)alamin" FT /ligand_id="ChEBI:CHEBI:28115" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" 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:0000256|PIRSR:PIRSR000381-1" FT BINDING 818 FT /ligand="methylcob(III)alamin" FT /ligand_id="ChEBI:CHEBI:28115" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" FT BINDING 822 FT /ligand="methylcob(III)alamin" FT /ligand_id="ChEBI:CHEBI:28115" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" FT BINDING 874 FT /ligand="methylcob(III)alamin" FT /ligand_id="ChEBI:CHEBI:28115" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" FT BINDING 962 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" FT BINDING 1160 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" FT BINDING 1215..1216 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000256|PIRSR:PIRSR000381-2" SQ SEQUENCE 1253 AA; 139191 MW; CFBD40BB66EBD75E CRC64; MKKTLQDEIE AILRKRIMVL DGGMGTMIQR YKLSEENFQG QEFKDHSRPL KGNNDILSIT QPDVIYQIHK EYLLAGADII ETNTFSSTSI AQADYGLEHL AYRMNKCSAD VARKAAEEIT LQTGVKRFVA GSLGPTNKTL SVSPSVERPD YRNITFDELV EAYQEQAKGL LDGGVDILLI ETIFDTANAK AALFALQKLF EENYASPRPI FISGTIVDKS GRTLSGQTGE AFVTSVSHSD PLCIGLNCAL GAAEMRPFIE TIGKCTTAYV LCYPNAGLPN TFGDYDETPA MMAMHLKDFA VDGLVNVVGG CCGSTPDHIR EIAEAVKNCK PRVPPDSVFE GHMLLSGLEP FRIGPYTNFV NIGERCNVAG SKKFAKLIMA GNYEEALSVA KVQVEMGAQV LDINMDDGML DGPSAMTKFC NFIASEPDIA KVPLCIDSSN FAVIEAGLKC CQGKCIVNSI SLKEGEEDFL EKARKIKKFG AAVVVMAFDE EGQATETDVK VSVCTRAYHL LVEKVGFNPN DIIFDPNILT IGTGMEEHNL YAINFIHATR VIKETLPGVR ISGGLSNLSF AFRGMDAIRE AMHGVFLYHA IKFGMDMGIV NAGSLPVYDD IHKDLLQLCE DLIWNRDAEA TEKLLRYAQT HGKGGKKVIQ TDEWRNGSIE ERLEYALVKG IEKHIVEDTE EARLNREKYP RPLNIIEGPL MNGMKVVGDL FGAGKMFLPQ VIKSARVMKK AVGHLIPFME KEREEARVLN GSVEEEDPYQ GTIVLATVKG DVHDIGKNIV GVVLGCNNFR VIDLGVMTPC DKILQAALDH KADIIGLSGL ITPSLDEMIF VAKEMERLAI KIPLLIGGAT TSRTHTAVKI APRYSAPVIH VLDASKSVVV CSQLLDENLK DDYFEEILEE YEDIRQDHYE SLKERKYLPL SQARKHSFHI DWLSEPHPVK PTFIGTQVFE DYNLQKLVDY IDWKPFFDVW QLRGKYPNRG FPKIFNDKAV GEEARKVYED AQNMLNILIS RKKLRARGVV GFWPAQSVQD DIHLYAEGAV PQAAEPIATF YGLRQQAEKD SSSTDPYHCL SDFVAPLHSG VRDYLGLFAV ACFGVEELSK AYEDDGDDYS SIMVKALGDR LAEAFAEELH ERVRRELWAY CGSEQLGVTD LRKLRYEGIR PAPGYPSQPD HTEKLTMWRL ANIEQATGIR LTESLAMAPA SAVSGLYFSN VKSKYFAVGK ISKDQIEDYA LRKNMSVAEV EKWLGPILGY DTD //