Q99707 (METH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Methionine synthase
EC=2.1.1.13

Alternative name(s):
5-methyltetrahydrofolate--homocysteine methyltransferase
Vitamin-B12 dependent methionine synthase
Short name=MS

Gene names

Name:

MTR

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1265 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate By similarity.
Catalytic activity	5-methyltetrahydrofolate + L-homocysteine = tetrahydrofolate + L-methionine.
Cofactor	Methylcobalamin (MeCBL). Binds 1 zinc ion per subunit By similarity.
Pathway	Amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine (MetH route): step 1/1.
Subcellular location	Cytoplasm.
Tissue specificity	Widely expressed. Expressed at the highest levels in pancreas, heart, brain, skeletal muscle and placenta. Expressed at lower levels in lung, liver and kidney.
Domain	Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin By similarity.
Involvement in disease	Methylcobalamin deficiency type G (cblG) [MIM:250940]: Autosomal recessive inherited disease that causes mental retardation, macrocytic anemia, and homocystinuria. Mild deficiency in MS activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects. MS mutations could also be involved in tumorigenesis. Note: The disease is caused by mutations affecting the gene represented in this entry. Folate-sensitive neural tube defects (FS-NTD) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.9 Ref.10
Miscellaneous	L-homocysteine is bound via the zinc atom By similarity.
Sequence similarities	Belongs to the vitamin-B12 dependent methionine synthase family. Contains 1 AdoMet activation domain. Contains 1 B12-binding domain. Contains 1 B12-binding N-terminal domain. Contains 1 Hcy-binding domain. Contains 1 pterin-binding domain.

Ontologies

Keywords
Biological process	Amino-acid biosynthesis Methionine biosynthesis
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Repeat
Ligand	Cobalamin Cobalt Metal-binding S-adenosyl-L-methionine Zinc
Molecular function	Methyltransferase Transferase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular nitrogen compound metabolic process Traceable author statement. Source: Reactome methylation Traceable author statement. Source: Reactome nervous system development Traceable author statement Ref.1. Source: ProtInc pteridine-containing compound metabolic process Inferred from electronic annotation. Source: InterPro sulfur amino acid metabolic process Traceable author statement. Source: Reactome xenobiotic metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	cobalamin binding Inferred from electronic annotation. Source: UniProtKB-KW homocysteine S-methyltransferase activity Inferred from electronic annotation. Source: InterPro methionine synthase activity Inferred from electronic annotation. Source: EC zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TSC22D1	Q15714	1	EBI-1045782,EBI-712609

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1265

1265

Methionine synthase

PRO_0000204530

Regions

Domain

19 – 338

320

Hcy-binding

Domain

371 – 632

262

Pterin-binding

Domain

662 – 759

98

B12-binding N-terminal

Domain

772 – 907

136

B12-binding

Domain

923 – 1265

343

AdoMet activation

Region

860 – 861

2

Cobalamin-binding By similarity

Region

1227 – 1228

2

S-adenosyl-L-methionine binding By similarity

Sites

Metal binding

260

1

Zinc By similarity

Metal binding

323

1

Zinc By similarity

Metal binding

324

1

Zinc By similarity

Metal binding

785

1

Cobalt (cobalamin axial ligand) By similarity

Binding site

830

1

Cobalamin By similarity

Binding site

974

1

S-adenosyl-L-methionine By similarity

Binding site

1172

1

S-adenosyl-L-methionine; via carbonyl oxygen By similarity

Binding site

1176

1

Cobalamin; via carbonyl oxygen By similarity

Natural variations

Natural variant

52

1

R → Q.
Corresponds to variant rs12749581 [ dbSNP | Ensembl ].

VAR_050033

Natural variant

61

1

R → K. Ref.8

VAR_004326

Natural variant

255

1

C → Y. Ref.3

VAR_004327

Natural variant

314

1

D → N.
Corresponds to variant rs2229274 [ dbSNP | Ensembl ].

VAR_061338

Natural variant

881

1

Missing in cblG. Ref.1 Ref.8

VAR_004328

Natural variant

919

1

D → G May be associated with susceptibility to FS-NTD. Ref.3 Ref.6 Ref.9 Ref.10
Corresponds to variant rs1805087 [ dbSNP | Ensembl ].

VAR_004329

Natural variant

920

1

H → D in cblG. Ref.1
Corresponds to variant rs28933097 [ dbSNP | Ensembl ].

VAR_004330

Natural variant

1173

1

P → L in cblG. Ref.8

VAR_004331

Secondary structure

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1265

Helix Strand Turn

Details...

Helix

932 – 937

6

Helix

944 – 946

3

Beta strand

956 – 962

7

Helix

966 – 970

5

Helix

976 – 987

12

Helix

995 – 998

4

Helix

1005 – 1022

18

Beta strand

1026 – 1040

15

Beta strand

1043 – 1046

4

Helix

1053 – 1055

3

Beta strand

1059 – 1063

5

Helix

1082 – 1085

4

Helix

1089 – 1091

3

Beta strand

1095 – 1106

12

Helix

1107 – 1116

10

Helix

1120 – 1147

28

Turn

1152 – 1155

4

Helix

1160 – 1164

5

Beta strand

1168 – 1171

4

Helix

1185 – 1192

8

Helix

1195 – 1199

5

Beta strand

1209 – 1220

12

Helix

1235 – 1245

11

Helix

1249 – 1255

7

Helix

1257 – 1259

3

Sequences

	Sequence		Length	Mass (Da)
	Q99707 [UniParc]. Last modified July 1, 1997. Version 2. Checksum: B04C26BCBE9A57C2	FASTA	1,265	140,527
	10 20 30 40 50 60 MSPALQDLSQ PEGLKKTLRD EINAILQKRI MVLDGGMGTM IQREKLNEEH FRGQEFKDHA 70 80 90 100 110 120 RPLKGNNDIL SITQPDVIYQ IHKEYLLAGA DIIETNTFSS TSIAQADYGL EHLAYRMNMC 130 140 150 160 170 180 SAGVARKAAE EVTLQTGIKR FVAGALGPTN KTLSVSPSVE RPDYRNITFD ELVEAYQEQA 190 200 210 220 230 240 KGLLDGGVDI LLIETIFDTA NAKAALFALQ NLFEEKYAPR PIFISGTIVD KSGRTLSGQT 250 260 270 280 290 300 GEGFVISVSH GEPLCIGLNC ALGAAEMRPF IEIIGKCTTA YVLCYPNAGL PNTFGDYDET 310 320 330 340 350 360 PSMMAKHLKD FAMDGLVNIV GGCCGSTPDH IREIAEAVKN CKPRVPPATA FEGHMLLSGL 370 380 390 400 410 420 EPFRIGPYTN FVNIGERCNV AGSRKFAKLI MAGNYEEALC VAKVQVEMGA QVLDVNMDDG 430 440 450 460 470 480 MLDGPSAMTR FCNLIASEPD IAKVPLCIDS SNFAVIEAGL KCCQGKCIVN SISLKEGEDD 490 500 510 520 530 540 FLEKARKIKK YGAAMVVMAF DEEGQATETD TKIRVCTRAY HLLVKKLGFN PNDIIFDPNI 550 560 570 580 590 600 LTIGTGMEEH NLYAINFIHA TKVIKETLPG ARISGGLSNL SFSFRGMEAI REAMHGVFLY 610 620 630 640 650 660 HAIKSGMDMG IVNAGNLPVY DDIHKELLQL CEDLIWNKDP EATEKLLRYA QTQGTGGKKV 670 680 690 700 710 720 IQTDEWRNGP VEERLEYALV KGIEKHIIED TEEARLNQKK YPRPLNIIEG PLMNGMKIVG 730 740 750 760 770 780 DLFGAGKMFL PQVIKSARVM KKAVGHLIPF MEKEREETRV LNGTVEEEDP YQGTIVLATV 790 800 810 820 830 840 KGDVHDIGKN IVGVVLGCNN FRVIDLGVMT PCDKILKAAL DHKADIIGLS GLITPSLDEM 850 860 870 880 890 900 IFVAKEMERL AIRIPLLIGG ATTSKTHTAV KIAPRYSAPV IHVLDASKSV VVCSQLLDEN 910 920 930 940 950 960 LKDEYFEEIM EEYEDIRQDH YESLKERRYL PLSQARKSGF QMDWLSEPHP VKPTFIGTQV 970 980 990 1000 1010 1020 FEDYDLQKLV DYIDWKPFFD VWQLRGKYPN RGFPKIFNDK TVGGEARKVY DDAHNMLNTL 1030 1040 1050 1060 1070 1080 ISQKKLRARG VVGFWPAQSI QDDIHLYAEA AVPQAAEPIA TFYGLRQQAE KDSASTEPYY 1090 1100 1110 1120 1130 1140 CLSDFIAPLH SGIRDYLGLF AVACFGVEEL SKAYEDDGDD YSSIMVKALG DRLAEAFAEE 1150 1160 1170 1180 1190 1200 LHERVRRELW AYCGSEQLDV ADLRRLRYKG IRPAPGYPSQ PDHTEKLTMW RLADIEQSTG 1210 1220 1230 1240 1250 1260 IRLTESLAMA PASAVSGLYF SNLKSKYFAV GKISKDQVED YALRKNISVA EVEKWLGPIL GYDTD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders." Leclerc D., Campeau E., Goyette P., Adjalla C.E., Christensen B., Ross M., Eydoux P., Rosenblatt D.S., Rozen R., Gravel R.A. Hum. Mol. Genet. 5:1867-1874(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS CBLG ILE-881 DEL AND ASP-920. Tissue: Fibroblast.
[2]	"Cloning, mapping and RNA analysis of the human methionine synthase gene." Li Y.N., Gulati S., Baker P.J., Brody L.C., Banerjee R., Kruger W.D. Hum. Mol. Genet. 5:1851-1858(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[3]	"Human methionine synthase. cDNA cloning, gene localization, and expression." Chen L.H., Liu M.-L., Hwang H.-Y., Chen L.-S., Korenberg J., Shane B. J. Biol. Chem. 272:3628-3634(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS TYR-255 AND GLY-919. Tissue: Fetal liver.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT GLY-919. Tissue: Testis.
[7]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[8]	"Defects in human methionine synthase in cblG patients." Gulati S., Baker P.J., Li Y.N., Fowler B., Kruger W.D., Brody L.C., Banerjee R. Hum. Mol. Genet. 5:1859-1865(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CBLG ILE-881 DEL AND LEU-1173, VARIANT LYS-61.
[9]	"Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida." Doolin M.-T., Barbaux S., McDonnell M., Hoess K., Whitehead A.S., Mitchell L.E. Am. J. Hum. Genet. 71:1222-1226(2002) [PubMed] [Europe PMC] [Abstract] Cited for: ASSOCIATION OF VARIANT GLY-919 WITH SUSCEPTIBILITY TO FS-NTD.
[10]	"Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association." O'Leary V.B., Mills J.L., Pangilinan F., Kirke P.N., Cox C., Conley M., Weiler A., Peng K., Shane B., Scott J.M., Parle-McDermott A., Molloy A.M., Brody L.C. Mol. Genet. Metab. 85:220-227(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NO ASSOCIATION OF VARIANT GLY-919 WITH SUSCEPTIBILITY TO FS-NTD.
+	Additional computationally mapped references.

Web resources

Wikipedia

5-methyltetrahydrofolate-homocysteine methyltransferase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U71285 mRNA. Translation: AAC51188.1.
U75743 mRNA. Translation: AAB58906.1.
U73338 mRNA. Translation: AAB39704.1.
AL359185, AL359259 Genomic DNA. Translation: CAH73198.1.
AL359259, AL359185 Genomic DNA. Translation: CAH70983.1.
CH471098 Genomic DNA. Translation: EAW70066.1.
BC130616 mRNA. Translation: AAI30617.1.
BC136440 mRNA. Translation: AAI36441.1.

IPI

IPI00743284.

RefSeq

NP_000245.2. NM_000254.2.

UniGene

Hs.498187.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2O2K	X-ray	1.60	A/B	925-1265	[»]

ProteinModelPortal

Q99707.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q99707. 1 interaction.

STRING

9606.ENSP00000355536.

PTM databases

PhosphoSite

Q99707.

Polymorphism databases

DMDM

2842762.

Proteomic databases

PaxDb

Q99707.

PRIDE

Q99707.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000366577; ENSP00000355536; ENSG00000116984.

GeneID

4548.

KEGG

hsa:4548.

UCSC

uc001hyi.4. human.

Organism-specific databases

CTD

4548.

GeneCards

GC01P236958.

HGNC

HGNC:7468. MTR.

HPA

HPA044474.

MIM

156570. gene.
250940. phenotype.
601634. phenotype.
603174. phenotype.

neXtProt

NX_Q99707.

Orphanet

2170. Methylcobalamin deficiency type cblG.
3388. Neural tube defect.

PharmGKB

PA31272.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1410.

HOGENOM

HOG000251409.

HOVERGEN

HBG006347.

InParanoid

Q99707.

KO

K00548.

OMA

VRKEFWG.

OrthoDB

EOG41JZBC.

PhylomeDB

Q99707.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

UniPathway

UPA00051; UER00081.

Gene expression databases

ArrayExpress

Q99707.

Bgee

Q99707.

CleanEx

HS_MTR.

Genevestigator

Q99707.

GermOnline

ENSG00000116984. Homo sapiens.

Family and domain databases

Gene3D

1.10.1240.10. 1 hit.
3.10.196.10. 1 hit.
3.20.20.20. 1 hit.
3.20.20.330. 1 hit.
3.40.50.280. 1 hit.

InterPro

IPR003759. Cbl-bd_cap.
IPR006158. Cobalamin-bd.
IPR011005. Dihydropteroate_synth-like.
IPR011822. MetH.
IPR000489. Pterin-binding.
IPR003726. S_MeTrfase.
IPR004223. VitB12-dep_Met_synth_activ_dom.
[Graphical view]

PANTHER

PTHR21091:SF9. PTHR21091:SF9. 1 hit.

Pfam

PF02310. B12-binding. 1 hit.
PF02607. B12-binding_2. 1 hit.
PF02965. Met_synt_B12. 1 hit.
PF00809. Pterin_bind. 1 hit.
PF02574. S-methyl_trans. 1 hit.
[Graphical view]

PIRSF

PIRSF000381. MetH. 1 hit.

SMART

SM01018. B12-binding_2. 1 hit.
[Graphical view]

SUPFAM

SSF52242. Cbl-bd. 1 hit.
SSF51717. DHP_synth_like. 1 hit.
SSF56507. Met_synth_B12. 1 hit.
SSF47644. Met_synth_Cbl-bd. 1 hit.
SSF82282. S_methyl_trans. 1 hit.

TIGRFAMs

TIGR02082. metH. 1 hit.

PROSITE

PS50974. ADOMET_ACTIVATION. 1 hit.
PS51332. B12_BINDING. 1 hit.
PS51337. B12_BINDING_NTER. 1 hit.
PS50970. HCY. 1 hit.
PS50972. PTERIN_BINDING. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

MTR. human.

DrugBank

DB00200. Hydroxocobalamin.
DB00134. L-Methionine.
DB00116. Tetrahydrofolic acid.

EvolutionaryTrace

Q99707.

GenomeRNAi

4548.

NextBio

17533.

SOURCE

Search...

Entry information

Entry name

METH_HUMAN

Accession

Primary (citable) accession number: Q99707
Secondary accession number(s): A1L4N8 , A9Z1W4, B9EGF7, Q99713, Q99723

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	July 1, 1997
Last modified:	May 1, 2013
This is version 135 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.