METH_HUMAN
ID METH_HUMAN Reviewed; 1265 AA.
AC Q99707; A1L4N8; A9Z1W4; B7ZLW7; B9EGF7; Q99713; Q99723;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 2.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=Methionine synthase {ECO:0000303|PubMed:8968737};
DE Short=MS;
DE EC=2.1.1.13 {ECO:0000269|PubMed:16769880, ECO:0000269|PubMed:17288554};
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:0000303|PubMed:27771510, ECO:0000312|HGNC:HGNC:7468};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANTS
RP HMAG ILE-881 DEL AND ASP-920.
RC TISSUE=Fibroblast;
RX PubMed=8968737; DOI=10.1093/hmg/5.12.1867;
RA Leclerc D., Campeau E., Goyette P., Adjalla C.E., Christensen B., Ross M.,
RA Eydoux P., Rosenblatt D.S., Rozen R., Gravel R.A.;
RT "Human methionine synthase: cDNA cloning and identification of mutations in
RT patients of the cblG complementation group of folate/cobalamin disorders.";
RL Hum. Mol. Genet. 5:1867-1874(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=8968735; DOI=10.1093/hmg/5.12.1851;
RA Li Y.N., Gulati S., Baker P.J., Brody L.C., Banerjee R., Kruger W.D.;
RT "Cloning, mapping and RNA analysis of the human methionine synthase gene.";
RL Hum. Mol. Genet. 5:1851-1858(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS TYR-255 AND GLY-919.
RC TISSUE=Fetal liver;
RX PubMed=9013615; DOI=10.1074/jbc.272.6.3444;
RA Chen L.H., Liu M.-L., Hwang H.-Y., Chen L.-S., Korenberg J., Shane B.;
RT "Human methionine synthase. cDNA cloning, gene localization, and
RT expression.";
RL J. Biol. Chem. 272:3628-3634(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP GLY-919.
RC TISSUE=Testis;
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 [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH MTRR.
RX PubMed=16769880; DOI=10.1073/pnas.0603694103;
RA Yamada K., Gravel R.A., Toraya T., Matthews R.G.;
RT "Human methionine synthase reductase is a molecular chaperone for human
RT methionine synthase.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:9476-9481(2006).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MMACHC; MMADHC AND
RP MTRR.
RX PubMed=27771510; DOI=10.1016/j.bbadis.2016.10.016;
RA Bassila C., Ghemrawi R., Flayac J., Froese D.S., Baumgartner M.R.,
RA Gueant J.L., Coelho D.;
RT "Methionine synthase and methionine synthase reductase interact with MMACHC
RT and with MMADHC.";
RL Biochim. Biophys. Acta 1863:103-112(2017).
RN [10]
RP VARIANTS HMAG ILE-881 DEL AND LEU-1173, AND VARIANT LYS-61.
RX PubMed=8968736; DOI=10.1093/hmg/5.12.1859;
RA Gulati S., Baker P.J., Li Y.N., Fowler B., Kruger W.D., Brody L.C.,
RA Banerjee R.;
RT "Defects in human methionine synthase in cblG patients.";
RL Hum. Mol. Genet. 5:1859-1865(1996).
RN [11]
RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT GLY-919.
RX PubMed=12375236; DOI=10.1086/344209;
RA Doolin M.-T., Barbaux S., McDonnell M., Hoess K., Whitehead A.S.,
RA Mitchell L.E.;
RT "Maternal genetic effects, exerted by genes involved in homocysteine
RT remethylation, influence the risk of spina bifida.";
RL Am. J. Hum. Genet. 71:1222-1226(2002).
RN [12]
RP VARIANT GLY-919.
RX PubMed=15979034; DOI=10.1016/j.ymgme.2005.02.003;
RA O'Leary V.B., Mills J.L., Pangilinan F., Kirke P.N., Cox C., Conley M.,
RA Weiler A., Peng K., Shane B., Scott J.M., Parle-McDermott A., Molloy A.M.,
RA Brody L.C.;
RT "Analysis of methionine synthase reductase polymorphisms for neural tube
RT defects risk association.";
RL Mol. Genet. Metab. 85:220-227(2005).
RN [13] {ECO:0007744|PDB:4CCZ}
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 16-657 IN COMPLEX WITH
RP TETRAHYDROFOLATE.
RA Vollmar M., Kiyani W., Krojer T., Goubin S., Burgess-Brown N.,
RA Von Delft F., Oppermann U., Edwards A., Arrowsmith C., Bountra C.,
RA Yue W.W.;
RT "Crystal structure of human 5-methyltetrahydrofolate-homocysteine
RT methyltransferase, the homocysteine and folate binding domains.";
RL Submitted (OCT-2013) to the PDB data bank.
RN [14] {ECO:0007744|PDB:2O2K}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 924-1265 OF MUTANT
RP GLU-963/ASN-1071, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, INTERACTION WITH
RP MTRR, AND MUTAGENESIS OF ASP-963 AND LYS-1071.
RX PubMed=17288554; DOI=10.1111/j.1742-4658.2006.05618.x;
RA Wolthers K.R., Toogood H.S., Jowitt T.A., Marshall K.R., Leys D.,
RA Scrutton N.S.;
RT "Crystal structure and solution characterization of the activation domain
RT of human methionine synthase.";
RL FEBS J. 274:738-750(2007).
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:16769880,
CC PubMed:27771510, PubMed:17288554). MeCbl is an active form of cobalamin
CC (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 (PubMed:16769880, PubMed:27771510,
CC PubMed:17288554). The processing of cobalamin in the cytosol occurs in
CC a 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 (PubMed:16769880, PubMed:27771510).
CC {ECO:0000269|PubMed:16769880, ECO:0000269|PubMed:17288554,
CC ECO:0000269|PubMed:27771510}.
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:0000269|PubMed:16769880, ECO:0000269|PubMed:17288554};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11173;
CC Evidence={ECO:0000269|PubMed:16769880, ECO:0000269|PubMed:17288554};
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:0000269|PubMed:27771510}.
CC -!- SUBUNIT: Monomer (PubMed:17288554). Dimer (PubMed:17288554). Forms a
CC multiprotein complex with MMACHC, MMADHC AND MTRR (PubMed:17288554,
CC PubMed:16769880, PubMed:27771510). {ECO:0000269|PubMed:16769880,
CC ECO:0000269|PubMed:17288554, ECO:0000269|PubMed:27771510}.
CC -!- INTERACTION:
CC Q99707; Q9Y4U1: MMACHC; NbExp=3; IntAct=EBI-1045782, EBI-9775184;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:27771510}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q99707-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q99707-2; Sequence=VSP_057283;
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at the highest levels
CC in pancreas, heart, brain, skeletal muscle and placenta
CC (PubMed:8968737, PubMed:8968735). Expressed at lower levels in lung,
CC liver and kidney (PubMed:8968737, PubMed:8968735).
CC {ECO:0000269|PubMed:8968735, ECO:0000269|PubMed:8968737}.
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 -!- DISEASE: Homocystinuria-megaloblastic anemia, cblG complementation type
CC (HMAG) [MIM:250940]: An autosomal recessive inborn error of metabolism
CC resulting from defects in the cobalamin-dependent pathway that converts
CC homocysteine to methionine. It causes delayed psychomotor development,
CC megaloblastic anemia, homocystinuria, and hypomethioninemia.
CC {ECO:0000269|PubMed:8968736, ECO:0000269|PubMed:8968737}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]:
CC The most common NTDs are open spina bifida (myelomeningocele) and
CC anencephaly. {ECO:0000269|PubMed:12375236}. Note=Disease susceptibility
CC is associated with variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the vitamin-B12 dependent methionine synthase
CC family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=5-methyltetrahydrofolate-
CC homocysteine methyltransferase entry;
CC URL="https://en.wikipedia.org/wiki/5-Methyltetrahydrofolate-homocysteine_methyltransferase";
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DR EMBL; U71285; AAC51188.1; -; mRNA.
DR EMBL; U75743; AAB58906.1; -; mRNA.
DR EMBL; U73338; AAB39704.1; -; mRNA.
DR EMBL; AL359185; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL359259; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471098; EAW70066.1; -; Genomic_DNA.
DR EMBL; BC130616; AAI30617.1; -; mRNA.
DR EMBL; BC136440; AAI36441.1; -; mRNA.
DR EMBL; BC144095; AAI44096.1; -; mRNA.
DR CCDS; CCDS1614.1; -. [Q99707-1]
DR CCDS; CCDS73054.1; -. [Q99707-2]
DR RefSeq; NP_000245.2; NM_000254.2. [Q99707-1]
DR RefSeq; NP_001278868.1; NM_001291939.1. [Q99707-2]
DR RefSeq; NP_001278869.1; NM_001291940.1.
DR PDB; 2O2K; X-ray; 1.60 A; A/B=925-1265.
DR PDB; 4CCZ; X-ray; 2.70 A; A=16-657.
DR PDBsum; 2O2K; -.
DR PDBsum; 4CCZ; -.
DR AlphaFoldDB; Q99707; -.
DR SMR; Q99707; -.
DR BioGRID; 110642; 116.
DR DIP; DIP-40306N; -.
DR IntAct; Q99707; 34.
DR MINT; Q99707; -.
DR STRING; 9606.ENSP00000355536; -.
DR BindingDB; Q99707; -.
DR ChEMBL; CHEMBL2150844; -.
DR DrugBank; DB00115; Cyanocobalamin.
DR DrugBank; DB00200; Hydroxocobalamin.
DR DrugBank; DB11256; Levomefolic acid.
DR DrugBank; DB03614; Mecobalamin.
DR DrugBank; DB00134; Methionine.
DR DrugBank; DB00116; Tetrahydrofolic acid.
DR DrugBank; DB11590; Thimerosal.
DR DrugCentral; Q99707; -.
DR GlyGen; Q99707; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q99707; -.
DR PhosphoSitePlus; Q99707; -.
DR BioMuta; MTR; -.
DR DMDM; 2842762; -.
DR EPD; Q99707; -.
DR jPOST; Q99707; -.
DR MassIVE; Q99707; -.
DR MaxQB; Q99707; -.
DR PaxDb; Q99707; -.
DR PeptideAtlas; Q99707; -.
DR PRIDE; Q99707; -.
DR ProteomicsDB; 7238; -.
DR ProteomicsDB; 78423; -. [Q99707-1]
DR Antibodypedia; 20817; 158 antibodies from 30 providers.
DR DNASU; 4548; -.
DR Ensembl; ENST00000366577.10; ENSP00000355536.5; ENSG00000116984.15. [Q99707-1]
DR Ensembl; ENST00000535889.6; ENSP00000441845.1; ENSG00000116984.15. [Q99707-2]
DR GeneID; 4548; -.
DR KEGG; hsa:4548; -.
DR MANE-Select; ENST00000366577.10; ENSP00000355536.5; NM_000254.3; NP_000245.2.
DR UCSC; uc001hyi.5; human. [Q99707-1]
DR CTD; 4548; -.
DR DisGeNET; 4548; -.
DR GeneCards; MTR; -.
DR GeneReviews; MTR; -.
DR HGNC; HGNC:7468; MTR.
DR HPA; ENSG00000116984; Low tissue specificity.
DR MalaCards; MTR; -.
DR MIM; 156570; gene.
DR MIM; 250940; phenotype.
DR MIM; 601634; phenotype.
DR MIM; 603174; phenotype.
DR neXtProt; NX_Q99707; -.
DR OpenTargets; ENSG00000116984; -.
DR Orphanet; 2170; Methylcobalamin deficiency type cblG.
DR PharmGKB; PA31272; -.
DR VEuPathDB; HostDB:ENSG00000116984; -.
DR eggNOG; KOG1579; Eukaryota.
DR GeneTree; ENSGT00420000029824; -.
DR HOGENOM; CLU_004914_1_0_1; -.
DR InParanoid; Q99707; -.
DR OMA; ADCIAMS; -.
DR OrthoDB; 1417203at2759; -.
DR PhylomeDB; Q99707; -.
DR TreeFam; TF312829; -.
DR BioCyc; MetaCyc:HS04076-MON; -.
DR BRENDA; 2.1.1.13; 2681.
DR PathwayCommons; Q99707; -.
DR Reactome; R-HSA-156581; Methylation.
DR Reactome; R-HSA-1614635; Sulfur amino acid metabolism.
DR Reactome; R-HSA-3359467; Defective MTRR causes HMAE.
DR Reactome; R-HSA-3359469; Defective MTR causes HMAG.
DR Reactome; R-HSA-9013407; RHOH GTPase cycle.
DR Reactome; R-HSA-9759218; Cobalamin (Cbl) metabolism.
DR SignaLink; Q99707; -.
DR SIGNOR; Q99707; -.
DR UniPathway; UPA00051; UER00081.
DR BioGRID-ORCS; 4548; 43 hits in 1083 CRISPR screens.
DR ChiTaRS; MTR; human.
DR EvolutionaryTrace; Q99707; -.
DR GeneWiki; Methionine_synthase; -.
DR GenomeRNAi; 4548; -.
DR Pharos; Q99707; Tbio.
DR PRO; PR:Q99707; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q99707; protein.
DR Bgee; ENSG00000116984; Expressed in caput epididymis and 214 other tissues.
DR ExpressionAtlas; Q99707; baseline and differential.
DR Genevisible; Q99707; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0031419; F:cobalamin binding; IEA:UniProtKB-KW.
DR GO; GO:0008705; F:methionine synthase activity; IDA:CACAO.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0031103; P:axon regeneration; ISS:BHF-UCL.
DR GO; GO:0071732; P:cellular response to nitric oxide; ISS:BHF-UCL.
DR GO; GO:0009235; P:cobalamin metabolic process; IMP:BHF-UCL.
DR GO; GO:0009086; P:methionine biosynthetic process; IMP:BHF-UCL.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0042558; P:pteridine-containing compound metabolic process; IEA:InterPro.
DR GO; GO:0048678; P:response to axon injury; ISS:BHF-UCL.
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 3D-structure; Alternative splicing; Amino-acid biosynthesis; Cobalamin;
KW Cobalt; Cytoplasm; Disease variant; Metal-binding; Methionine biosynthesis;
KW Methyltransferase; Phosphoprotein; Reference proteome; Repeat;
KW S-adenosyl-L-methionine; Transferase; Zinc.
FT CHAIN 1..1265
FT /note="Methionine synthase"
FT /id="PRO_0000204530"
FT DOMAIN 19..338
FT /note="Hcy-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT DOMAIN 371..632
FT /note="Pterin-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00334"
FT DOMAIN 662..759
FT /note="B12-binding N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00667"
FT DOMAIN 772..907
FT /note="B12-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00666"
FT DOMAIN 923..1265
FT /note="AdoMet activation"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00346"
FT BINDING 260
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT BINDING 323
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT BINDING 324
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00333"
FT BINDING 382..384
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:4CCZ"
FT BINDING 449
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:4CCZ"
FT BINDING 470
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:4CCZ"
FT BINDING 537
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:4CCZ"
FT BINDING 579
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:4CCZ"
FT BINDING 585
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:4CCZ"
FT BINDING 591
FT /ligand="(6S)-5,6,7,8-tetrahydrofolate"
FT /ligand_id="ChEBI:CHEBI:57453"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PDB:4CCZ"
FT BINDING 709
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 782..786
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 785
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 830
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 834
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 886
FT /ligand="methylcob(III)alamin"
FT /ligand_id="ChEBI:CHEBI:28115"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 974
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 1172
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT BINDING 1227..1228
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P13009"
FT MOD_RES 1264
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z2Q4"
FT VAR_SEQ 682..732
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_057283"
FT VARIANT 52
FT /note="R -> Q (in dbSNP:rs12749581)"
FT /id="VAR_050033"
FT VARIANT 61
FT /note="R -> K"
FT /evidence="ECO:0000269|PubMed:8968736"
FT /id="VAR_004326"
FT VARIANT 255
FT /note="C -> Y (in dbSNP:rs1140598)"
FT /evidence="ECO:0000269|PubMed:9013615"
FT /id="VAR_004327"
FT VARIANT 314
FT /note="D -> N (in dbSNP:rs2229274)"
FT /id="VAR_061338"
FT VARIANT 881
FT /note="Missing (in HMAG)"
FT /evidence="ECO:0000269|PubMed:8968736,
FT ECO:0000269|PubMed:8968737"
FT /id="VAR_004328"
FT VARIANT 919
FT /note="D -> G (in dbSNP:rs1805087)"
FT /evidence="ECO:0000269|PubMed:12375236,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:15979034,
FT ECO:0000269|PubMed:9013615"
FT /id="VAR_004329"
FT VARIANT 920
FT /note="H -> D (in HMAG; dbSNP:rs121913579)"
FT /evidence="ECO:0000269|PubMed:8968737"
FT /id="VAR_004330"
FT VARIANT 1173
FT /note="P -> L (in HMAG; dbSNP:rs121913578)"
FT /evidence="ECO:0000269|PubMed:8968736"
FT /id="VAR_004331"
FT MUTAGEN 963
FT /note="D->E: Decreases binding to MTRR; when associated
FT with N-1071."
FT /evidence="ECO:0000269|PubMed:17288554"
FT MUTAGEN 1071
FT /note="K->N: Decreases binding to MTRR; when associated
FT with E-963."
FT /evidence="ECO:0000269|PubMed:17288554"
FT HELIX 18..28
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 37..44
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 49..51
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 67..69
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 70..73
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 75..87
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 92..94
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 102..105
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 106..108
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 111..113
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 114..136
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 141..146
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 153..155
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 159..161
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 169..185
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 189..198
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 199..213
FT /evidence="ECO:0007829|PDB:4CCZ"
FT TURN 214..216
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 222..226
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 241..248
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 249..251
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 254..263
FT /evidence="ECO:0007829|PDB:4CCZ"
FT TURN 264..267
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 268..275
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 279..287
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 318..320
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 328..338
FT /evidence="ECO:0007829|PDB:4CCZ"
FT TURN 348..353
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 355..365
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 372..375
FT /evidence="ECO:0007829|PDB:4CCZ"
FT TURN 380..382
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 384..391
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 395..407
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 411..416
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 424..437
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 439..442
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 446..449
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 453..462
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 468..472
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 478..491
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 494..501
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 509..527
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 531..533
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 534..537
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 548..552
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 553..567
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 577..584
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 588..605
FT /evidence="ECO:0007829|PDB:4CCZ"
FT STRAND 609..612
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 620..622
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 625..635
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 642..648
FT /evidence="ECO:0007829|PDB:4CCZ"
FT HELIX 932..937
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 944..946
FT /evidence="ECO:0007829|PDB:2O2K"
FT STRAND 956..962
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 966..970
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 976..987
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 995..998
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1005..1022
FT /evidence="ECO:0007829|PDB:2O2K"
FT STRAND 1026..1040
FT /evidence="ECO:0007829|PDB:2O2K"
FT STRAND 1043..1046
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1053..1055
FT /evidence="ECO:0007829|PDB:2O2K"
FT STRAND 1059..1063
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1082..1085
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1089..1091
FT /evidence="ECO:0007829|PDB:2O2K"
FT STRAND 1095..1106
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1107..1116
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1120..1147
FT /evidence="ECO:0007829|PDB:2O2K"
FT TURN 1152..1155
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1160..1164
FT /evidence="ECO:0007829|PDB:2O2K"
FT STRAND 1168..1171
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1185..1192
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1195..1199
FT /evidence="ECO:0007829|PDB:2O2K"
FT STRAND 1209..1220
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1235..1245
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1249..1255
FT /evidence="ECO:0007829|PDB:2O2K"
FT HELIX 1257..1259
FT /evidence="ECO:0007829|PDB:2O2K"
SQ SEQUENCE 1265 AA; 140527 MW; B04C26BCBE9A57C2 CRC64;
MSPALQDLSQ PEGLKKTLRD EINAILQKRI MVLDGGMGTM IQREKLNEEH FRGQEFKDHA
RPLKGNNDIL SITQPDVIYQ IHKEYLLAGA DIIETNTFSS TSIAQADYGL EHLAYRMNMC
SAGVARKAAE EVTLQTGIKR FVAGALGPTN KTLSVSPSVE RPDYRNITFD ELVEAYQEQA
KGLLDGGVDI LLIETIFDTA NAKAALFALQ NLFEEKYAPR PIFISGTIVD KSGRTLSGQT
GEGFVISVSH GEPLCIGLNC ALGAAEMRPF IEIIGKCTTA YVLCYPNAGL PNTFGDYDET
PSMMAKHLKD FAMDGLVNIV GGCCGSTPDH IREIAEAVKN CKPRVPPATA FEGHMLLSGL
EPFRIGPYTN FVNIGERCNV AGSRKFAKLI MAGNYEEALC VAKVQVEMGA QVLDVNMDDG
MLDGPSAMTR FCNLIASEPD IAKVPLCIDS SNFAVIEAGL KCCQGKCIVN SISLKEGEDD
FLEKARKIKK YGAAMVVMAF DEEGQATETD TKIRVCTRAY HLLVKKLGFN PNDIIFDPNI
LTIGTGMEEH NLYAINFIHA TKVIKETLPG ARISGGLSNL SFSFRGMEAI REAMHGVFLY
HAIKSGMDMG IVNAGNLPVY DDIHKELLQL CEDLIWNKDP EATEKLLRYA QTQGTGGKKV
IQTDEWRNGP VEERLEYALV KGIEKHIIED TEEARLNQKK YPRPLNIIEG PLMNGMKIVG
DLFGAGKMFL PQVIKSARVM KKAVGHLIPF MEKEREETRV LNGTVEEEDP YQGTIVLATV
KGDVHDIGKN IVGVVLGCNN FRVIDLGVMT PCDKILKAAL DHKADIIGLS GLITPSLDEM
IFVAKEMERL AIRIPLLIGG ATTSKTHTAV KIAPRYSAPV IHVLDASKSV VVCSQLLDEN
LKDEYFEEIM EEYEDIRQDH YESLKERRYL PLSQARKSGF QMDWLSEPHP VKPTFIGTQV
FEDYDLQKLV DYIDWKPFFD VWQLRGKYPN RGFPKIFNDK TVGGEARKVY DDAHNMLNTL
ISQKKLRARG VVGFWPAQSI QDDIHLYAEA AVPQAAEPIA TFYGLRQQAE KDSASTEPYY
CLSDFIAPLH SGIRDYLGLF AVACFGVEEL SKAYEDDGDD YSSIMVKALG DRLAEAFAEE
LHERVRRELW AYCGSEQLDV ADLRRLRYKG IRPAPGYPSQ PDHTEKLTMW RLADIEQSTG
IRLTESLAMA PASAVSGLYF SNLKSKYFAV GKISKDQVED YALRKNISVA EVEKWLGPIL
GYDTD
