MetaCyc Pathway: S-adenosyl-L-methionine cycle II
Inferred from experiment

Enzyme View:

Pathway diagram: S-adenosyl-L-methionine cycle II

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.

Synonyms: activated methyl cycle, SAM cycle

Superclasses: BiosynthesisAmino Acids BiosynthesisProteinogenic Amino Acids BiosynthesisL-methionine BiosynthesisL-methionine SalvageS-adenosyl-L-methionine cycle

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Camellia sinensis, Catharanthus roseus, Lupinus luteus, Mycobacterium tuberculosis, Rattus norvegicus

Expected Taxonomic Range: Bacteria , Eukaryota

About 20% of the L-methionine pool is used as a building block of proteins. The rest is converted to S-adenosyl-L-methionine (SAM), the major methyl donor in the cell. When SAM donates its methyl group, it is converted to S-adenosyl-L-homocysteine. This molecule can be recycled back to SAM via the S-adenosyl-L-methionine cycle, also known as the activated methyl cycle (AMC).

There are two main variations of this pathway, one found mostly in prokaryotes, while the other is found predominantly, but not exclusively, in eukaryotes (for example, it operates in Mycobacterium tuberculosis [Reddy08]. The main difference between the variants is the processing of S-adenosyl-L-homocysteine (SAH), the immediate product of the methylation reactions.

In the first pathway (described in S-adenosyl-L-methionine cycle I) SAH is first hydrolyzed to S-ribosyl-L-homocysteine by the MTA/SAH nucleosidase, followed by conversion to L-homocysteine by S-ribosylhomocysteine lyase. In the second pathway, which is described in S-adenosyl-L-methionine cycle II, SAH is hydrolyzed to L-homocysteine in a single step, catalyzed by S-adenosylhomocysteine hydrolase.

The cycle continues with the methylation of L-homocysteine to L-methionine using a methyl group from a methylated folate. In some organisms, including Homo sapiens, this reaction is catalyzed by a cobalamin-dependent methionine synthase (EC In other organisms, such as Bacillus subtilis, the reaction is catalyzed by a cobalamin-independent methionine synthase (EC Yet some organisms, such as Escherichia coli and Corynebacterium glutamicum, have both enzymes, as described in the pathway L-methionine biosynthesis III. In Escherichia coli the reaction catalyzed by the B12-dependent enzyme is more than 100-fold faster than the reaction catalyzed by the B12-independent isoenzyme [Rodionov04].

Finally, the cycle is completed with the regeneration of SAM by S-adenosylmethionine synthetase.

About S-adenosylhomocysteine hydrolase: While the reaction catalyzed by this enzyme is reversible, the equilibrium favors the synthesis of S-adenosyl-L-homocysteine. Thus the removal of the hydrolysis product L-homocysteine is critical for the continuous operation of the cycle. This is achieved by the efficient conversion of L-homocysteine to L-methionine via methionine synthase.

Variants: S-adenosyl-L-methionine cycle I

Unification Links: AraCyc:PWY-5041

Revised 09-Mar-2009 by Caspi R, SRI International


Koshiishi01: Koshiishi C, Kato A, Yama S, Crozier A, Ashihara H (2001). "A new caffeine biosynthetic pathway in tea leaves: utilisation of adenosine released from the S-adenosyl-L-methionine cycle." FEBS Lett 499(1-2);50-4. PMID: 11418110

Reddy08: Reddy MC, Kuppan G, Shetty ND, Owen JL, Ioerger TR, Sacchettini JC (2008). "Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors." Protein Sci 17(12);2134-44. PMID: 18815415

Rodionov04: Rodionov DA, Vitreschak AG, Mironov AA, Gelfand MS (2004). "Comparative genomics of the methionine metabolism in Gram-positive bacteria: a variety of regulatory systems." Nucleic Acids Res 32(11);3340-53. PMID: 15215334

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

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

Brzezinski01: Brzezinski K, Janowski R, Podkowinski J, Jaskolski M (2001). "Sequence determination and analysis of S-adenosyl-L-homocysteine hydrolase from yellow lupine (Lupinus luteus)." Acta Biochim Pol 48(2);477-83. PMID: 11732617

Cabrero87: Cabrero C, Puerta J, Alemany S (1987). "Purification and comparison of two forms of S-adenosyl-L-methionine synthetase from rat liver." Eur J Biochem 170(1-2);299-304. PMID: 3121322

Chattopadhyay91: Chattopadhyay MK, Ghosh AK, Sengupta S (1991). "Control of methionine biosynthesis in Escherichia coli K12: a closer study with analogue-resistant mutants." J Gen Microbiol 137(3);685-91. PMID: 2033383

Chiang77: Chiang PK, Cantoni GL (1977). "Activation of methionine for transmethylation. Purification of the S-adenosylmethionine synthetase of bakers' yeast and its separation into two forms." J Biol Chem 1977;252(13);4506-13. PMID: 194884

Chou72: Chou TC, Talalay P (1972). "The mechanism of S-adenosyl-L-methionine synthesis by purified preparations of bakers' yeast." Biochemistry 1972;11(6);1065-73. PMID: 4552214

Csaikl86: Csaikl U, Csaikl F (1986). "Molecular cloning and characterization of the MET6 gene of Saccharomyces cerevisiae." Gene 46(2-3);207-14. PMID: 3542720

Eichel95: Eichel J, Gonzalez JC, Hotze M, Matthews RG, Schroder J (1995). "Vitamin-B12-independent methionine synthase from a higher plant (Catharanthus roseus). Molecular characterization, regulation, heterologous expression, and enzyme properties." Eur J Biochem 230(3);1053-8. PMID: 7601135

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

Fujioka81: Fujioka M, Takata Y (1981). "S-Adenosylhomocysteine hydrolase from rat liver. Purification and some properties." J Biol Chem 256(4);1631-5. PMID: 7462216

Gakiere99: Gakiere B, Job D, Douce R, Ravanel S "Characterization of the cDNA and Gene for a Cytosolic Cobalamin-Independent Methionine Synthase in Arabidopsis thaliana (Accession No. U97200). (PGR99-115)." Plant Physiol. (1999), 120, 1206.

Gomi85: Gomi T, Ishiguro Y, Fujioka M (1985). "S-Adenosylhomocysteinase from rat liver. Evidence for structurally identical and catalytically equivalent subunits." J Biol Chem 260(5);2789-93. PMID: 3972804

Gonzalez03: Gonzalez B, Pajares MA, Hermoso JA, Guillerm D, Guillerm G, Sanz-Aparicio J (2003). "Crystal structures of methionine adenosyltransferase complexed with substrates and products reveal the methionine-ATP recognition and give insights into the catalytic mechanism." J Mol Biol 331(2);407-16. PMID: 12888348

Greene73: Greene RC, Hunter JS, Coch EH (1973). "Properties of metK mutants of Escherichia coli K-12." J Bacteriol 115(1);57-67. PMID: 4577753

Grundy02: Grundy,F.J., Henkin,T.M. (2002). "Synthesis of serine, glycine, cysteine, and methionine." in Sonenshein,A.L., Hoch,J.A. and Losick,R. (eds), Bacillus subtilis and its Relatives: From Genes to Cells. American Society for Microbiology, Washington, DC, pp. 245254.

Guest64: Guest JR, Friedman S, Foster MA, Tejerina G, Woods DD (1964). "Transfer of the methyl group from N5-methyltetrahydrofolates to homocysteine in Escherichia coli." Biochem J 92(3);497-504. PMID: 5319972

Guranowski77a: Guranowski A, Pawelkiewicz J (1977). "Adenosylhomocysteinase from yellow lupin seeds. Purification and properties." Eur J Biochem 80(2);517-23. PMID: 923592

Hansen97: Hansen J, Muldbjerg M, Cherest H, Surdin-Kerjan Y (1997). "Siroheme biosynthesis in Saccharomyces cerevisiae requires the products of both the MET1 and MET8 genes." FEBS Lett 401(1);20-4. PMID: 9003798

Hiroki97: Hiroki T, Horikawa S, Tsukada K (1997). "Structure of the rat methionine adenosyltransferase 2A gene and its promoter." Eur J Biochem 250(3);653-60. PMID: 9461287

Horikawa89: Horikawa S, Ishikawa M, Ozasa H, Tsukada K (1989). "Isolation of a cDNA encoding the rat liver S-adenosylmethionine synthetase." Eur J Biochem 184(3);497-501. PMID: 2806235

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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
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