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methionine synthase; 5-methyltetrahydrofolate:homocysteine methyltransferase; vitamin-B12 dependent methionine synthase; tetrahydropteroyl-glutamate methyltransferase; MS (MTR)

Function: - one of 2 vitamin B12-dependent enzymes in mammals - catalyzes methylcobalamin-dependent transfer of methyl group from N5-methyl tetrahydrofolate to homocysteine to form methionine & tetrahydrofolate. - in connection with 5,10-methylenetetrahydrofolate reductase activity which generates N5-methyltetrahydrofolate, methionine synthase regulates methionine synthesis & tetrahydrofolate generation - availability of tetrahydrofolate is critical to DNA generation - amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine 5-methyltetrahydrofolate + L-homocysteine tetrahydrofolate + L-methionine Cofactor: methylcobalamin (MeCBL) Structure: - 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 methylation of cobalamin by methyltetrahydrofolate & the methylation of homocysteine - the B12-binding domain binds the cofactor - binds 1 Zn+2 per subunit (putative) - L-homocysteine is bound via Zn+2 - the AdoMet activation domain binds S-adenosyl-L-methionine - under aerobic conditions cobalamin [Co+] can be converted to inactive cobalamin [Co+2] - reductive methylation by S-adenosyl-L-methionine & flavodoxin regenerates methylcobalamin - 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 Compartment: cytoplasm Expression: - widely expressed - expressed at the highest levels in pancreas, heart, brain, skeletal muscle & placenta - expressed at lower levels in lung, liver & kidney Pathology: - defects in MTR are the cause of a) methylcobalamin deficiency type G b) susceptibility to folate-sensitive neural tube defects c) hyperhomocysteinemia d) may paly role in tumorigenesis

Interactions

molecular events

Related

5,10-methylenetetrahydrofolate reductase (MTHFR) folate metabolism homocysteine methionine methionine metabolism (trans-sulfuration pathway) methylcobalamin (vitamin B12) MTR gene mutation N5-methyltetrahydrofolate tetrahydrofolate (THF)

General

N-methyltransferase S-methyltransferase

Properties

SIZE: entity length = 1265 aa MW = 141 kD COMPARTMENT: cytoplasm MOTIF: binding site SITE: 19-338 FOR-BINDING-OF: HCY MOTIF: Zn+2-binding site SITE: 260-260 Zn+2-binding site SITE: 323-323 Zn+2-binding site SITE: 324-324 binding site SITE: 371-632 FOR-BINDING-OF: pterin active site binding site SITE: 662-759 FOR-BINDING-OF: cobalamin binding site SITE: 772-907 FOR-BINDING-OF: methylcobalamin MOTIF: binding site SITE: 830-830 FOR-BINDING-OF: Cobalamin binding site SITE: 860-861 FOR-BINDING-OF: methylcobalamin AdoMet activation {923-1265} MOTIF: binding site SITE: 974-974 FOR-BINDING-OF: S-adenosylmethionine binding site SITE: 1172-1172 FOR-BINDING-OF: S-adenosylmethionine binding site SITE: 1176-1176 FOR-BINDING-OF: methylcobalamin S-adenosyl-L-methionine binding {1227-1228}

Database Correlations

OMIM correlations UniProt Q99707 PFAM correlations Entrez Gene 4548 KEGG correlations ENZYME 2.1.1.13

References

  1. Stryer Biochemistry WH Freeman & Co, New York, 1988 pg 508, 583
  2. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 2200
  3. UniProt :accession Q99707
  4. Wikipedia; 5-methyltetrahydrofolate-homocysteine methyltransferase entry http://en.wikipedia.org/wiki/5-methyltetrahydrofolate-homocysteine_methyltransferase