METH_RAT
ID METH_RAT Reviewed; 1253 AA.
AC Q9Z2Q4;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Methionine synthase {ECO:0000303|PubMed:9972236};
DE Short=MS;
DE EC=2.1.1.13 {ECO:0000269|PubMed:9219091, ECO:0000269|PubMed:9972236};
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;
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;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RC STRAIN=Wistar; TISSUE=Liver;
RX PubMed=9972236; DOI=10.1271/bbb.62.2155;
RA Yamada K., Tobimatsu T., Toraya T.;
RT "Cloning, sequencing, and heterologous expression of rat methionine
RT synthase cDNA.";
RL Biosci. Biotechnol. Biochem. 62:2155-2160(1998).
RN [2]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1252, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
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]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=9219091; DOI=10.3177/jnsv.43.177;
RA Yamada K., Tobimatsu T., Kawata T., Wada M., Maekawa A., Toraya T.;
RT "Purification and some properties of cobalamin-dependent methionine
RT synthase from rat liver.";
RL J. Nutr. Sci. Vitaminol. 43:177-186(1997).
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 (PubMed:9219091,
CC PubMed:9972236). MeCbl is an active form of cobalamin (vitamin B12)
CC used as a cofactor for methionine biosynthesis (PubMed:9219091,
CC PubMed:9972236). Cob(I)alamin form is regenerated to MeCbl by a
CC transfer of a methyl group from 5-methyltetrahydrofolate (By
CC similarity). The processing of cobalamin in the cytosol occurs in a
CC multiprotein complex composed of at least MMACHC, MMADHC, MTRR
CC (methionine synthase reductase) and MTR which may contribute to shuttle
CC safely and efficiently cobalamin towards MTR in order to produce
CC methionine (By similarity). {ECO:0000250|UniProtKB:Q99707,
CC ECO:0000269|PubMed:9219091, ECO:0000269|PubMed:9972236}.
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; Evidence={ECO:0000269|PubMed:9219091,
CC ECO:0000269|PubMed:9972236};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11173;
CC Evidence={ECO:0000305|PubMed:9219091};
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 -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=75 uM for (6S)-5-methyl-5,6,7,8-tetrahydrofolate
CC {ECO:0000269|PubMed:9219091};
CC KM=1.7 uM for L-homocysteine {ECO:0000269|PubMed:9219091};
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:0000305|PubMed:9219091}.
CC -!- SUBUNIT: Monomer (PubMed:9219091). Dimer. Forms a multiprotein complex
CC with MMACHC, MMADHC AND MTRR. {ECO:0000250|UniProtKB:Q99707,
CC ECO:0000269|PubMed:9219091}.
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; AF034214; AAD05384.1; -; mRNA.
DR PIR; T42376; T42376.
DR RefSeq; NP_110491.1; NM_030864.1.
DR AlphaFoldDB; Q9Z2Q4; -.
DR SMR; Q9Z2Q4; -.
DR BioGRID; 249519; 1.
DR IntAct; Q9Z2Q4; 1.
DR STRING; 10116.ENSRNOP00000023973; -.
DR CarbonylDB; Q9Z2Q4; -.
DR iPTMnet; Q9Z2Q4; -.
DR PhosphoSitePlus; Q9Z2Q4; -.
DR PaxDb; Q9Z2Q4; -.
DR PRIDE; Q9Z2Q4; -.
DR GeneID; 81522; -.
DR KEGG; rno:81522; -.
DR UCSC; RGD:621283; rat.
DR CTD; 4548; -.
DR RGD; 621283; Mtr.
DR eggNOG; KOG1579; Eukaryota.
DR InParanoid; Q9Z2Q4; -.
DR OrthoDB; 731388at2759; -.
DR PhylomeDB; Q9Z2Q4; -.
DR BRENDA; 2.1.1.13; 5301.
DR Reactome; R-RNO-156581; Methylation.
DR Reactome; R-RNO-1614635; Sulfur amino acid metabolism.
DR Reactome; R-RNO-9013407; RHOH GTPase cycle.
DR Reactome; R-RNO-9759218; Cobalamin (Cbl) metabolism.
DR UniPathway; UPA00051; UER00081.
DR PRO; PR:Q9Z2Q4; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0016597; F:amino acid binding; IDA:RGD.
DR GO; GO:0031419; F:cobalamin binding; TAS:RGD.
DR GO; GO:0005542; F:folic acid binding; IDA:RGD.
DR GO; GO:0008705; F:methionine synthase activity; IDA:RGD.
DR GO; GO:0008168; F:methyltransferase activity; IDA:RGD.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0061431; P:cellular response to methionine; IEP:RGD.
DR GO; GO:0009235; P:cobalamin metabolic process; ISO:RGD.
DR GO; GO:0050667; P:homocysteine metabolic process; IDA:RGD.
DR GO; GO:0009086; P:methionine biosynthetic process; IDA:RGD.
DR GO; GO:0006555; P:methionine metabolic process; IMP:RGD.
DR GO; GO:0006479; P:protein methylation; IDA:RGD.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; IDA:RGD.
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_0000312902"
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:0007744|PubMed:22673903"
SQ SEQUENCE 1253 AA; 139164 MW; 96BD40B796EBD75B 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 AQNMLSILIS 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
