This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Amino Acids Biosynthesis → Individual Amino Acids Biosynthesis → Methionine Biosynthesis → Methionine Salvage|
Expected Taxonomic Range: Mammalia
Methionine is an essential amino acid in mammals. It is not biosynthesized and must be obtained in the diet. Methionine, or its metabolites, participate in fundamental processes such as protein synthesis, S-adenosylmethionine-dependent transmethylations, polyamine formation, cysteine biosynthesis, and homocysteine biosynthesis which is necessary for folate and choline metabolism (reviewed in [Finkelstein90]). Its major routes of metabolism in mammalian liver involve transmethylation and transsulfuration pathways. In the transmethylation pathway methionine is converted to S-adenosyl-L-methionine, a compound that participates in most biological methylation reactions.
S-adenosylmethionine is demethylated to S-adenosylhomocysteine, which is reversibly hydrolyzed to homocysteine and adenosine, see methionine degradation I (to homocysteine). High levels of homocysteine are toxic, and further metabolism of homocysteine is required. Methylation of homocysteine regenerates methionine.
About this Pathway
Homocysteine is a branch point between methionine degradative and biosynthetic pathways. The conservation of homocysteine completes a "methionine cycle" (reviewed in [Griffith87, Finkelstein90, Stipanuk04a]). Hyperhomocysteinemia in humans has been associated with an increased risk of cardiovascular disease [Medina01].
In humans and rodents approximately half of the homocysteine formed condenses with L-serine to form L-cystathionine via the transsulfuration pathway cysteine biosynthesis/homocysteine degradation [Finkelstein84]. The remainder is remethylated to methionine via three salvage reactions. As shown here, one involves methionine synthase, which uses N5-methyl-tetrahydropteroyl mono-L-glutamate as the methyl donor [Chen97a]. A second reaction involves betaine--homocysteine S-methyltransferase, which uses glycine betaine as the methyl donor [Garrow96]. The third reaction involves S-methylmethionine homocysteine methyltransferase which uses S-methyl-L-methionine as the methyl donor [Szegedi08].
Superpathways: superpathway of methionine salvage and degradation
Szegedi08: Szegedi SS, Castro CC, Koutmos M, Garrow TA (2008). "Betaine-homocysteine S-methyltransferase-2 is an S-methylmethionine-homocysteine methyltransferase." J Biol Chem 283(14);8939-45. PMID: 18230605
Balish67: Balish E, Shapiro SK (1967). "Methionine biosynthesis in Escherichia coli: induction and repression of methylmethionine(or adenosylmethionine):homocysteine methyltransferase." Arch Biochem Biophys 119(1);62-8. PMID: 4861151
Banerjee89: Banerjee RV, Johnston NL, Sobeski JK, Datta P, Matthews RG (1989). "Cloning and sequence analysis of the Escherichia coli metH gene encoding cobalamin-dependent methionine synthase and isolation of a tryptic fragment containing the cobalamin-binding domain." J Biol Chem 1989;264(23);13888-95. PMID: 2668277
Banerjee90: Banerjee RV, Frasca V, Ballou DP, Matthews RG (1990). "Participation of cob(I) alamin in the reaction catalyzed by methionine synthase from Escherichia coli: a steady-state and rapid reaction kinetic analysis." Biochemistry 1990;29(50);11101-9. PMID: 2271698
Bose02: Bose N, Greenspan P, Momany C (2002). "Expression of recombinant human betaine: homocysteine S-methyltransferase for x-ray crystallographic studies and further characterization of interaction with S-adenosylmethionine." Protein Expr Purif 25(1);73-80. PMID: 12071701
Chadwick00: Chadwick LH, McCandless SE, Silverman GL, Schwartz S, Westaway D, Nadeau JH (2000). "Betaine-homocysteine methyltransferase-2: cDNA cloning, gene sequence, physical mapping, and expression of the human and mouse genes." Genomics 70(1);66-73. PMID: 11087663
DelgadoReyes01: Delgado-Reyes CV, Wallig MA, Garrow TA (2001). "Immunohistochemical detection of betaine-homocysteine S-methyltransferase in human, pig, and rat liver and kidney." Arch Biochem Biophys 393(1);184-6. PMID: 11516176
Evans02: Evans JC, Huddler DP, Jiracek J, Castro C, Millian NS, Garrow TA, Ludwig ML (2002). "Betaine-homocysteine methyltransferase: zinc in a distorted barrel." Structure 10(9);1159-71. PMID: 12220488
Forestier03: Forestier M, Banninger R, Reichen J, Solioz M (2003). "Betaine homocysteine methyltransferase: gene cloning and expression analysis in rat liver cirrhosis." Biochim Biophys Acta 1638(1);29-34. PMID: 12757931
Frasca88: Frasca V, Banerjee RV, Dunham WR, Sands RH, Matthews RG (1988). "Cobalamin-dependent methionine synthase from Escherichia coli B: electron paramagnetic resonance spectra of the inactive form and the active methylated form of the enzyme." Biochemistry 27(22);8458-65. PMID: 2853966
Gonzalez04: Gonzalez B, Pajares MA, Martinez-Ripoll M, Blundell TL, Sanz-Aparicio J (2004). "Crystal structure of rat liver betaine homocysteine s-methyltransferase reveals new oligomerization features and conformational changes upon substrate binding." J Mol Biol 338(4);771-82. PMID: 15099744
Goulding97: Goulding CW, Postigo D, Matthews RG (1997). "Cobalamin-dependent methionine synthase is a modular protein with distinct regions for binding homocysteine, methyltetrahydrofolate, cobalamin, and adenosylmethionine." Biochemistry 36(26);8082-91. PMID: 9201956
Goulding97a: Goulding CW, Matthews RG (1997). "Cobalamin-dependent methionine synthase from Escherichia coli: involvement of zinc in homocysteine activation." Biochemistry 1997;36(50);15749-57. PMID: 9398304
Leclerc98: Leclerc D, Wilson A, Dumas R, Gafuik C, Song D, Watkins D, Heng HH, Rommens JM, Scherer SW, Rosenblatt DS, Gravel RA (1998). "Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria." Proc Natl Acad Sci U S A 95(6);3059-64. PMID: 9501215
Lee92b: Lee KH, Cava M, Amiri P, Ottoboni T, Lindquist RN (1992). "Betaine:homocysteine methyltransferase from rat liver: purification and inhibition by a boronic acid substrate analog." Arch Biochem Biophys 292(1);77-86. PMID: 1370132
Liptak07: Liptak MD, Fleischhacker AS, Matthews RG, Brunold TC (2007). "Probing the role of the histidine 759 ligand in cobalamin-dependent methionine synthase." Biochemistry 46(27);8024-35. PMID: 17567043
Luschinsky92: Luschinsky CL, Drummond JT, Matthews RG, Ludwig ML (1992). "Crystallization and preliminary X-ray diffraction studies of the cobalamin-binding domain of methionine synthase from Escherichia coli." J Mol Biol 1992;225(2);557-60. PMID: 1593636
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