S‐Adenosylmethionine

Abstract

S‐adenosylmethionine is one of the few sulfonium ions found in nature and it plays essential roles in the metabolism of all known organisms. The positively charged sulfonium centre endows S‐adenosylmethionine with a chemical versatility matched by few other biochemicals, perhaps exceeding even adenosine triphosphate (ATP). S‐adenosylmethionine is used in a multitude of metabolic pathways, and the types of chemical reactions in which it partakes are highly varied, ranging from alkylation to free‐radical formation. S‐sdenosylmethionine is methyl donor in many biosynthetic reactions, whereas methylation of both deoxyribonucleic acid(DNA) and proteins is part of the epigenetic control of cell growth and development. In other pathways, the propylamine moiety is incorporated into the pervasive polyamines spermidine and spermine. Unusual reactions consume S‐adenosylmethionine in the formation of plant growth factor ethylene, of cyclopropane fatty acids and in sulfur insertion in the biosynthesis of biotin, lipoic acid and thiamine. S‐adenosylmethionine appears to be one of the molecules required for life.

Key concepts:

  • S‐adenosylmethionine is a branch point compound with components from purine, amino acid and reduced sulfur metabolism, and thus is potentially able to coordinate these three areas of metabolism. S‐adenosylmethionine appears to be required for life.

  • The sulfonium centre of S‐adenosylmethionine is able to transfer any of the three attached alkyl groups, providing a metabolic versatility matched by few other biological molecules.

  • S‐adenosylmethionine is a progenitor of free radicals that occur as protein‐bound reaction intermediates in unusual chemical transformations catalysed by the ‘Radical SAM’: family of enzymes.

  • S‐adenosylmethionine metabolism is commonly disrupted in liver disease, and hereditary defects have been found in a few patients with abnormal sulfur metabolism.

  • S‐adenosylmethionine is under investigation as a potential drug in treatment of depression, arthritis and liver disease.

Keywords: coenzymes and cofactors; methylation; free radicals; nucleosides; quorum sensing; polyamines

Figure 1.

Structure of S‐adenosylmethionine (AdoMet or SAM). The sulfur of l‐methionine is connected in a sulfonium linkage to the carbon 5′ of 5′‐deoxyadenosine that is derived from ATP. The stereochemical configuration at the sulfur in enyzmatically formed S‐adenosylmethionine is (S); however S‐adenosylmethionine spontaneously racemises to the inactive (R)‐isomer over a period of a few days. The carbons attached to the positively charged sulfur are electrophilic and readily transferred to basic compounds.

Figure 2.

Illustration of metabolic roles of S‐adenosylmethionine. The predominant sulfur‐containing products of biosynthesis are S‐adenosylhomocysteine (SAH) and 5′‐methylthioadenosine (MTA), which have important roles in metabolic regulation as well as the cellular conservation and interconversion of reduced sulfur.

close

References

Agger K, Christensen J, Cloos PA and Helin K (2008) The emerging functions of histone demethylases. Current Opinion in Genetics and Development 18: 159–168.

Bedford MT and Richard S (2005) Arginine methylation an emerging regulator of protein function. Molecular Cell 18: 263–272.

Booker SJ, Cicchillo RM and Grove TL (2007) Self‐sacrifice in radical S‐adenosylmethionine proteins. Current Opinion in Genetics and Development 11: 543–552.

Bottiglieri T (2002) S‐Adenosyl‐L‐methionine (SAMe): from the bench to the bedside: molecular basis of a pleiotrophic molecule. American Journal of Clinical Nutrition 76: 1151S–1157S.

Cantoni GL (1953) S‐adenosylmethionine: a new intermediate formed enzymatically from L‐methionine and adenosine triphosphate. Journal of Biological Chemistry 204: 403–446.

Cheng X and Blumenthal RM (1999) S‐adenosylmethionine‐dependent Methyltransferases: Structures and Functions. Singapore: World Scientific.

Cheng X and Roberts RJ (2001) AdoMet‐dependent methylation, DNA methyltransferases and base flipping. Nucleic Acids Research 29: 3784–3795.

Cheng X and Zhang X (2007) Structural dynamics of protein lysine methylation and demethylation. Mutation Research 618: 102–115.

Choi JY, Lee TW, Jeon KW and Ahn TI (1997) Evidence for symbiont‐induced alteration of a host's gene expression: irreversible loss of SAM synthetase from Amoeba proteus. Journal of Eukaryotic Microbiology 44: 412–419.

Clarke S (2003) Aging as war between chemical and biochemical processes: protein methylation and the recognition of age‐damaged proteins for repair. Ageing Research Reviews 2: 263–285.

Deng H and O'Hagan D (2008) The fluorinase, the chlorinase and the duf‐62 enzymes. Current Opinion in Chemical Biology 12: 582–592.

Floss HG and Tsai MD (1979) Chiral methyl groups. Advances in Enzymology and Related Areas of Molecular Biology 50: 243–302.

Fontecave M, Atta M and Mulliez E (2004) S‐adenosylmethionine: nothing goes to waste. Trends in Biochemical Sciences 29: 243–249.

Frey PA and Booker SJ (2001) Radical mechanisms of S‐adenosylmethionine‐dependent enzymes. Advances in Protein Chemistry 58: 1–45.

Graham DE, Bock CL, Schalk‐Hihi C, Lu ZJ and Markham GD (2000) Identification of a highly diverged class of S‐adenosylmethionine synthetases in the archaea. Journal of Biological Chemistry 275: 4055–4059.

Hackert ML and Pegg AE (1997) Pyruvoyl‐dependent enzymes. In: Sinnott M (ed.) Comprehensive Biochemical Catalysis, pp. 210–216. New York: Academic Press.

Hegazi MF, Borchardt RT and Schowen RL (1979) Alpha‐deuterium and carbon‐13 isotope effects for methyl transfer catalyzed by catechol‐O‐methyl‐transferase SN 2‐like transition state. Journal of the American Chemical Society 101: 4359–4365.

Kotb M and Kredich NM (1985) S‐adenosylmethionine synthetase from human lymphocytes. Purification and characterization. Journal of Biological Chemistry 260: 3923–3930.

Markham GD and Pajares MA (2009) Structure‐function relationships in methionine adenosyltransferases. Cellular and Molecular Life Sciences 66: 636–648.

Merali S and Clarkson AB Jr (2004) S‐adenosylmethionine and pneumocystis. FEMS Microbiology Letters 237: 179–186.

Mudd SH (1973) The adenosyltransferases. In: Boyer PD (ed.) The Enzymes, pp. 121–154. New York: Academic Press.

O'Hagan D, Schaffrath C, Cobb SL, Hamilton JT and Murphy CD (2002) Biochemistry: biosynthesis of an organofluorine molecule. Nature 416: 279.

Rice JC and Allis CD (2001) Histone methylation versus histone acetylation: new insights into epigenetic regulation. Current Opinion in Cell Biology 13: 263–273.

Tabor CW and Tabor H (1984) Polyamines. Annual Review of Biochemistry 53: 749–790.

Tamas I, Klasson LM, Sandstrom JP and Andersson SG (2001) Mutualists and parasites: how to paint yourself into a (metabolic) corner. FEBS Letters 498: 135–139.

Thompson PR and Fast W (2006) Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock? ACS Chemical Biology 1: 433–441.

Tomsic J, McDaniel BA, Grundy FJ and Henkin TM (2008) Natural variability in S‐adenosylmethionine (SAM)‐dependent riboswitches: S‐box elements in Bacillus subtilis exhibit differential sensitivity to SAM in vivo and in vitro. Journal of Bacteriology 190: 823–833.

Wang SC and Frey PA (2007) S‐adenosylmethionine as an oxidant: the radical SAM superfamily. Trends in Biochemical Sciences 32: 101–110.

Waters CM and Bassler BL (2005) Quorum sensing: cell‐to‐cell communication in bacteria. Annual Review of Cell and Developmental Biology 21: 319–346.

Further Reading

Borchardt RT, Creveling CR and Ueland PM (1986) Biological Methylation and Drug Design: Experimental and Clinical Role of S‐adenosylmethionine (Experimental Biology and Medicine). Clifton, NJ: Humana Press.

Brown R, Colman C and Bottiglieri T (2000) Stop Depression Now: Sam‐E: The Breakthrough Supplement That Works as Well as Prescription Drugs, in Half the Time with No Side Effects. New York: Berkley Publishing Group.

Chiang PK, Gordon RK, Tal J et al. (1996) S‐adenosylmethionine and methylation. FASEB Journal 10: 471–480.

Cohen SS (1998) A Guide to the Polyamines. New York: Oxford University Press.

Grogan DW and Cronan JE Jr (1997) Cyclopropane ring formation in membrane lipids of bacteria. Microbiology and Molecular Biology Reviews 61: 429–441.

Martinez‐Lopez N, Varela‐Rey M, Ariz U et al. (2008) S‐adenosylmethionine and proliferation: new pathways, new targets. Biochemical Society Transactions 36: 848–852.

Online Mendelian Inheritance in Man (OMIM) (2006) Methionine adenosyltransferase deficiency. MIM Number: 250850, 26 October. Johns Hopkins University, Baltimore, MD. http://www.ncbi.nlm.nih.gov/omim. Accessed in February 2010.

Paik WK, Paik DC and Kim S (2007) Historical review: the field of protein methylation. Trends in Biochemical Science 32: 146–152.

Ravanel S, Gakiere B, Job D and Douce R (1998) The specific features of methionine biosynthesis and metabolism in plants. Proceedings of the National Academy of Sciences of the USA 95: 7805–7812.

Sekowska A, Kung HF and Danchin A (2000) Sulphur metabolism in E. coli and related bacteria: facts and fiction. Journal of Molecular Microbiology and Biotechnology 2: 145–177.

Thomas D and Surdin‐Kerjan Y (1997) Metabolism of sulphur amino acids in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews 61: 503–532.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Markham, George D(Apr 2010) S‐Adenosylmethionine. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000662.pub2]