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0METH_HUMAN*   SwissProt (?) | Description Local Annotation Link Reference
General Information
NameMTR
DescriptionMethionine synthase (ec 2.1.1.13) (5-methyltetrahydrofolate-- homocysteine methyltransferase) (methionine synthase, vitamin-b12 dependent) (ms).
SpeciesHomo sapiens (NCBI taxonomy ID: 9606)
GO0007399 neurogenesis (TAS)
Domain Architecture (Details)
InterPro domains unassigned to SynO:
Vitamin B12 dependent methionine synthase (5-methyltetrahydrofolate--homocysteine S-methyltransferase) catalyses the conversion of 5-methyltetrahydrofolate and L-homocysteine to tetrahydrofolate and L-methionine as the final step in de novo methionine biosynthesis. The enzyme requires methylcobalamin as a cofactor. In humans.efects in this enzyme are the cause of autosomal recessive inherited methylcobalamin deficiency (CBLG).hich causes mental retardation.acrocytic anemia and homocystinuria. Mild deficiencies in activity may result in mild hyperhomocysteinemia.nd mutations in the enzyme may be involved in tumorigenesis. Vitamin B12 dependent methionine synthase is found in prokaryotes and eukaryotes.ut in prokaryotes the cofactor is cobalamin.In Escherichia coli.ethionine synthase is a large enzyme composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and tetrahydrofolate.he third module binds the B12 cofactor (..nd the C-terminal module (activation domain) binds S-adenosylmethionine. The activation domain is essential for the reductive activation of the enzyme. During the catalytic cycle.he highly reactive cob(I)alamin intermediate can be oxidised to produce an inactive cob(II)alamin enzyme; the enzyme is then reactivated via reductive methylation by the activation domain . The activation domain adopts an unusual alpha/beta fold.
  IPR004223:Vitamin B12 dependent methionine synthase, activation region
All organisms require reduced folate cofactors for the synthesis of a variety of metabolites. Most microorganisms must synthesize folate de novo because they lack the active transport system of higher vertebrate cells that allows these organisms to use dietary folates. Proteins containing this domain include dihydropteroate synthase () as well as a group of methyltransferase enzymes including methyltetrahydrofolate.orrinoid iron-sulphur protein methyltransferase (MeTr) that catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation.Dihydropteroate synthase () (DHPS) catalyses the condensation of 6-hydroxymethyl-7.-dihydropteridine pyrophosphate to para-aminobenzoic acid to form 7.-dihydropteroate. This is the second step in the three-step pathway leading from 6-hydroxymethyl-7.-dihydropterin to 7.-dihydrofolate. DHPS is the target of sulphonamides.hich are substrate analogues that compete with para-aminobenzoic acid. Bacterial DHPS (gene sul or folP) is a protein of about 275 to 315 amino acid residues that is either chromosomally encoded or found on various antibiotic resistance plasmids. In the lower eukaryote Pneumocystis carinii.HPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas) .
  IPR000489:Dihydropteroate synthase, DHPS
Cobalamin-dependent methionine synthase () is a large modular protein that catalyses methyl transfer from methyltetrahydrofolate (CH3-H4folate) to homocysteine. During the catalytic cycle.t supports three distinct methyl transfer reactions.ach involving the cobalamin (vitamin B12) cofactor and a substrate bound to its own functional unit . The cobalamin cofactor plays an essential role in this reaction.ccepting the methyl group from CH3-H4folate to form methylcob(III)alamin.nd in turn donating the methyl group to homocysteine to generate methionine and cob(I)alamin.Methionine synthase is a large enzyme composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and CH3-H4folate.he third module binds the cobalamin cofactor and the C-terminal module binds S-adenosylmethionine. The cobalamin-binding module is composed of two structurally distinct domains: a 4-helical bundle cap domain (residues 651-740 in the Escherichia coli enzyme) and an alpha/beta B12-binding domain (residues 741-896) (). The 4-helical bundle forms a cap over the alpha/beta domain.hich acts to shield the methyl ligand of cobalamin from solvent . Furthermore.n the conversion to the active conformation of this enzyme.he 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain (). The alpha/beta domain is a common cobalamin-binding motif.hereas the 4-helical bundle domain with its methyl cap is a distinctive feature of methionine synthases.This entry represents the 4-helical bundle cap domain. This domain is also present in other shorter proteins that bind to B12.nd is always found N-terminus to the alpha/beta B12-binding domain.
  IPR003759:Methionine synthase, B12-binding module, cap
S-methylmethionine: homocysteine methyltransferase from Escherichia coli accepts selenohomocysteine as a substrate. S-methylmethionine is an abundant plant product that can be utilized for methionine biosynthesis . Human methionine synthase (5-methyltetrahydrofolate:L-homocysteine S-transmethylase; ) shares 53 and 63% identity with the E. coli and the presumptive Caenorhabditis elegans proteins.espectively.nd contains all residues implicated in B12 binding to the E. coli protein . Betaine--homocysteine S-methyltransferase () converts betaine and homocysteine to dimethylglycine and methionine.espectively. This reaction is also required for the irreversible oxidation of choline .
  IPR003726:Homocysteine S-methyltransferase
The cobalamin (vitamin B12) binding domain has an alpha/beta fold that is a common motif found in several different cobalamin-binding proteins. Proteins containing this domain include methionine synthase.he small subunit of glutamate mutase .nd the alpha and beta subunits of methylmalonyl-CoA mutase. In methionine synthase.here is a second.djacent domain involved in cobalamin binding that forms a 4-helical bundle cap (); in the conversion to the active conformation of this enzyme.he 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain () .The core structure of the cobalamin domain consists of 5 parallel beta-sheets.urrounded by 4-5 alpha helices in three layers.lpha/beta/alpha . The fold of the domain resembles that of the nucleotide-binding proteins (a Rossman fold). Upon binding B12.mportant elements of the binding site appear to become structured.ncluding an alpha-helix that forms on one side of the cleft accommodating the nucleotide tail of the cofactor.
  IPR006158:Cobalamin vitamin B12-binding
All organisms require reduced folate cofactors for the synthesis of a variety of metabolites. The enzyme 7.-dihydropteroate synthase (DHPS) () catalyses the condensation of para-aminobenzoic acid (pABA) with 6-hydroxymethyl-7.-dihydropterin-pyrophosphate to form 7.-dihydropteroate and pyrophosphate. DHPS is essential for the de novo synthesis of folate in prokaryotes.ower eukaryotes.nd in plants.ut is absent in mammals . By contrast.igher vertebrates possess an active transport system that enables them to use dietary folates. DHPS is the target of sulphonamides.hich are substrate analogues that compete with pABA.ut which do not affect vertebrates as they lack the DHPS enzyme. DHPS is a single domain protein that forms an eight-stranded TIM alpha/beta barrel.here the 7.-dihydropterin pyrophosphate substrate binds in a deep cleft in the barrel . In the lower eukaryote Pneumocystis carinii.HPS is the C-terminal domain of a multifunctional folate synthesis enzyme (gene fas) .Other proteins contain a DHPS-like domain.ncluding members of the methyltetrahydrofolate (corrinoid iron-sulphur protein methyltransferase (MeTr)) family. MeTr catalyses a key step in the Wood-Ljungdahl pathway of carbon dioxide fixation . Other members of this family that contain a DHPS-like domain include methionine synthase and methanogenic enzymes that activate the methyl group of methyltetrahydromethano(or -sarcino)pterin.The SSF signature in this entry is currently under review. Please be aware that some of the protein hits may be false positives.
  IPR011005:Dihydropteroate synthase-like
Vitamin B12 dependent methionine synthase (5-methyltetrahydrofolate--homocysteine S-methyltransferase) catalyses the conversion of 5-methyltetrahydrofolate and L-homocysteine to tetrahydrofolate and L-methionine as the final step in de novo methionine biosynthesis. The enzyme requires methylcobalamin as a cofactor. In humans.efects in this enzyme are the cause of autosomal recessive inherited methylcobalamin deficiency (CBLG).hich causes mental retardation.acrocytic anemia and homocystinuria. Mild deficiencies in activity may result in mild hyperhomocysteinemia.nd mutations in the enzyme may be involved in tumorigenesis. Vitamin B12 dependent methionine synthase is found in prokaryotes and eukaryotes.ut in prokaryotes the cofactor is cobalamin.This enzyme is a large protein composed of four structurally and functionally distinct modules: the first two modules bind homocysteine and tetrahydrofolate .he third module binds the B12 cofactor .nd the C-terminal module (activation domain) binds S-adenosylmethionine. The activation domain is essential for the reductive activation of the enzyme. During the catalytic cycle.he highly reactive cob(I)alamin intermediate can be oxidised to produce an inactive cob(II)alamin enzyme; the enzyme is then reactivated via reductive methylation by the activation domain . The activation domain adopts an unusual alpha/beta fold.Recent studies suggest that this enzyme exists as an ensemble of conformations with equilibria dependent on the oxidation and methylation state of the cobalamin and on the concentrations of substrates or products .
  IPR011822:5-methyltetrahydrofolate--homocysteine methyltransferase
IPR003726:S-methyl_trans 
Evalue:-163.721252441406 
Location:30-340IPR004223:Met_synt_B12 
Evalue:-75.5376052856445 
Location:1094-1230IPR000489:Pterin_bind 
Evalue:-75.3872146606445 
Location:371-586IPR003759:B12-binding_2 
Evalue:-47.8538703918457 
Location:669-755IPR006158:B12-binding 
Evalue:-24.3565464019775 
Location:773-884
SequencesProtein: METH_HUMAN (1265 aa)
mRNA: NM_000254
Local Annotation
Synapse Ontology
?
sdb:0265 cAMP mediated STP  (Evidence:keywords)
KO assignmentK00548
  Level 3 annotation:
    5-methyltetrahydrofolate--homocysteine methyltransferase
  Level 2 annotation:
    Methionine metabolism
    One carbon pool by folate
Loci Structure (Details)Loci index, Chromosomal location, Length, Possible relational loci clusterExon1: 107 residues, 235025340-235025660Exon2: 73 residues, 235033350-235033565Exon3: 32 residues, 235036066-235036156Exon4: 25 residues, 235038626-235038696Exon5: 33 residues, 235040425-235040518Exon6: 37 residues, 235042660-235042767Exon7: 22 residues, 235045526-235045586Exon8: 33 residues, 235046371-235046466Exon9: 35 residues, 235054041-235054142Exon10: 22 residues, 235055260-235055322Exon11: 24 residues, 235056751-235056819Exon12: 28 residues, 235059111-235059191Exon13: 39 residues, 235061888-235062001Exon14: 49 residues, 235065469-235065610Exon15: 64 residues, 235068336-235068522Exon16: 62 residues, 235080266-235080446Exon17: 41 residues, 235082443-235082560Exon18: 49 residues, 235082870-235083011Exon19: 32 residues, 235089755-235089845Exon20: 53 residues, 235091047-235091200Exon21: 38 residues, 235092158-235092266Exon22: 35 residues, 235093376-235093477Exon23: 24 residues, 235103695-235103763Exon24: 42 residues, 235104648-235104769Exon25: 29 residues, 235110677-235110759Exon26: 35 residues, 235115043-235115142Exon27: 27 residues, 235116214-235116290Exon28: 54 residues, 235119103-235119259Exon29: 67 residues, 235121055-235121252Exon30: 69 residues, 235124279-235124480Exon31: 66 residues, 235125280-235125473Exon32: 39 residues, 235126928-235127041Exon33: 1036 residues, 235127480-235130583Exon34: 2 residues, -Jump to METH_HUMAN  
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