MetaCyc Pathway: L-methionine salvage from L-homocysteine
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: L-methionine salvage from L-homocysteine

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: BiosynthesisAmino Acids BiosynthesisProteinogenic Amino Acids BiosynthesisL-methionine BiosynthesisL-methionine Salvage

Some taxa known to possess this pathway include : Homo sapiens, Rattus norvegicus

Expected Taxonomic Range: Mammalia

General Background

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 L-methionine degradation I (to L-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, Stipanuk04]). 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 L-cysteine biosynthesis III (from L-homocysteine) [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 [Chen97]. 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 L-methionine salvage and degradation

Revised 16-Sep-2013 by Weerasinghe D, SRI International


Banerjee90a: Banerjee RV, Matthews RG (1990). "Cobalamin-dependent methionine synthase." FASEB J 1990;4(5);1450-9. PMID: 2407589

Chen97: Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B (1997). "Human methionine synthase. cDNA cloning, gene localization, and expression." J Biol Chem 272(6);3628-34. PMID: 9013615

Duerre81: Duerre JA, Briske-Anderson M (1981). "Effect of adenosine metabolites on methyltransferase reactions in isolated rat livers." Biochim Biophys Acta 678(2);275-82. PMID: 7317453

Finkelstein84: Finkelstein JD, Martin JJ (1984). "Methionine metabolism in mammals. Distribution of homocysteine between competing pathways." J Biol Chem 259(15);9508-13. PMID: 6746658

Finkelstein90: Finkelstein JD (1990). "Methionine metabolism in mammals." J Nutr Biochem 1(5);228-37. PMID: 15539209

Garrow96: Garrow TA (1996). "Purification, kinetic properties, and cDNA cloning of mammalian betaine-homocysteine methyltransferase." J Biol Chem 271(37);22831-8. PMID: 8798461

Griffith87: Griffith OW (1987). "Mammalian sulfur amino acid metabolism: an overview." Methods Enzymol 143;366-76. PMID: 3309559

Medina01: Medina M, Urdiales JL, Amores-Sanchez MI (2001). "Roles of homocysteine in cell metabolism: old and new functions." Eur J Biochem 268(14);3871-82. PMID: 11453979

Stipanuk04: Stipanuk MH (2004). "Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine." Annu Rev Nutr 24;539-77. PMID: 15189131

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Balish66: Balish E, Shapiro SK (1966). "Cystathionine as a precursor of methionine in Escherichia coli and Aerobacter aerogenes." J Bacteriol 92(5);1331-6. PMID: 5332398

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

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

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

Fleischhacker07: Fleischhacker AS, Matthews RG (2007). "Ligand trans influence governs conformation in cobalamin-dependent methionine synthase." Biochemistry 46(43);12382-92. PMID: 17924667

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

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

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

Lee92a: 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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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Wed May 4, 2016, biocyc13.