S-Adenosylmethionine

George D Markham, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia,
PA, USA

Secondary article
Article Contents
. Biosynthesis and Transport How Cells Get Their SAdenosylmethionine . Where Does S-Adenosylmethionine Go? . S-Adenosylmethionine as Methyl Donor . Polyamine Biosynthesis . 5-Deoxyadenosyl Group Transfer . Other Alkylations by S-Adenosylmethionine . Radical S-Adenosylmethionine . S-Adenosylmethionine in Signalling . The Other Roles of S-Adenosylmethionine . Medical Aspects

S-Adenosylmethionine is one of the few sulfonium ions found in nature. The positively charged sulfonium centre endows S-adenosylmethionine with a chemical versatility matched by few other biochemicals, perhaps only adenosine triphosphate (ATP). Thus, not only is S-adenosylmethionine used in a multitude of metabolic pathways, but the types of chemical reactions in which it partakes are highly varied, ranging from alkylation to free radical formation. S-Adenosylmethionine and its metabolites play essential roles in the metabolism of all known organisms; it appears to be one of the molecules required for life.

Biosynthesis and Transport How Cells Get Their S-Adenosylmethionine

S-Adenosylmethionine (Figure 1) (variously represented as AdoMet, SAM or SAM-e) was reported by Cantoni (1953) as the chemical structure of the activated methyl donor whose existence was known from the studies of du Vigneaud. Subsequently the biosynthesis of S-adenosylmethionine was determined to be eected from adenosine triphosphate (ATP) and methionine in a reaction that remains unique in known biochemistry (eqn [I]). ATP 1 l-methionine 1 H2OxSAM 1 PPi 1 Pi [I]

The only other known biochemical reaction in which the entire tripolyphosphate chain is displaced from ATP occurs in formation of the bond between C5 of the adenosyl moiety and a cobalt atom in the synthesis of adenosylcobalamin (Mudd, 1973). In vivo, the inorganic
NH2

N N H H3C H2 C H3+N H O O C H2 H OH OH S+ CH2 H O H H N H

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 5deoxyadenosine that is derived from ATP. The stereochemical configuration at the sulfur in enyzmatically formed S-adenosylmethionine is (S); however S-adenosylmethionine spontaneously racemizes to the (R)isomer over a period of a few days. The carbons attached to the positively charged sulfur are electrophilic and readily transferred.

pyrophosphate (PPi) formed concomitantly with S-adenosylmethionine is hydrolysed by inorganic pyrophosphatase to two equivalents of phosphate (Pi). Consequently, the synthesis of S-adenosylmethionine is metabolically costly owing to consumption of all three phosphoryl groups of ATP. The requirement for PPi hydrolysis has been ascribed to a need to thermodynamically favour product formation because of the highenergy nature of the sulfonium moiety. The enzyme that catalyses this S-adenosylmethionine formation, S-adenosylmethionine synthetase (also known as methionine adenosyltransferase, ATP:l -methionine Sadenosyltransferase, often abbreviated MAT) occurs in two very distinct homologues that are distributed along evolutionary lines: the sequence of one form is highly conserved within both bacteria and eukarya, and another form is highly conserved within archaea (Graham et al., 2000). Eukarya typically have two or more isozymes with similar sequences but dierent expression proles. Crystallographic studies have shown the conserved topologies and active-site structures of the bacterial (Escherichia coli) and eukaryal (rat liver) MAT (Protein Data Bank (PDB) codes 1mxb and 1qm4, respectively). The complete genome sequences of the intracellular parasites Rickettsia prowazekii and Chlamydia trachomatis revealed them to lack functional S-adenosylmethionine synthetases, implying that they import S-adenosylmethionine from their hosts. Conversely, biochemical studies revealed the lack of a functional host S-adenosylmethionine synthetase in a strain of Amoeba proteus that harbours a bacterial symbiont that provides this function (Choi et al., 1997). The variety of spontaneous mutations that have accumulated in the nonfunctional version of the Rickettsia gene that once encoded S-adenosylmethionine synthetase (metK) illustrate the process of restriction of genome size through degradation of no longer essential genes (Tamas et al., 2001). S-Adenosylmethionine transport systems are present in the fungal pathogen Pneumocystis carinii, which
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S-Adenosylmethionine

is an S-adenosylmethionine auxotroph. Some organisms, such as trypanosomes and S. cerevisiae, possess the capability to import S-adenosylmethionine from their environment as well as to synthesize it. Enteric bacteria such as Escherichia coli are impermeable to S-adenosylmethionine. The extent of transport of S-adenosylmethionine in mammals remains unclear. Genomic sequencing and metabolic studies have substantiated that S-adenosylmethionine is required by even the most primitive characterized organisms. It may be considered as one of the molecules requisite for life as we know it.

Methylation of RNA provides diverse modications, with biological consequences that are varied and often unclear. Methylation of the N7 of guanine is involved in capping of eukaryotic messenger RNA, which is important for mRNA stability and nuclear export. Numerous methylation modications of transfer RNAs are known but, like many tRNA modications, their precise functions commonly remain elusive. Ribosomal RNAs are methylated on the 2-hydroxyls of specic residues, which aects RNA splicing, a process that is guided by small nucleolar RNAs in eukarya.

Where Does S-Adenosylmethionine Go?

Some of the metabolic pathways involving S-adenosylmethionine are outlined in Figure 2. Several reviews of Sadenosylmethionine metabolism in particular groups of organisms are listed in the Further Reading section.

Protein methylation
Proteins have been found that are methylated on a variety of polar side-chains, including the carboxylates of aspartate and glutamate, the sulfurs of cysteine and methionine, the imidazole of histidine, the amides of glutamine and asparagine, the guanidinium of arginine, the e-amino group of lysine, and terminal amino and carboxylate groups (Clarke, 1993). Multiple methylations can occur on the same arginine or lysine side-chain, leading to symmetrical and unsymmetrical dimethylarginine and di-or trimethyllysine. Methyl groups have been found on carbon-2 of a glutamine and carbon-4 of an arginine in the crystal structure of methyl-coenzyme M reductase from Methanobacterium thermoautotrophicum, a protein that also has 3-methylhistidine and S-methylcysteine residues (PDB code 1hbu). Notably absent are reports of Omethyltyrosine, O-methylserine and O-methylthreonine, three amino acids that are often phosphorylated in regulatory roles. Carboxylate methylation is involved in the regulation of a variety of metabolic processes. The ready hydrolysis of carboxymethyl esters makes these modications suitable for transient signalling. In bacterial chemotaxis, the reversible methylation of chemoreceptor glutamates is involved in sensing nutrient gradients. Carboxylate methylation of protein isoaspartyl groups that are formed by spontaneous rearrangements of aspartate and asparagine residues is a step in a series of reactions that regenerate an aspartate residue (with elimination of the methyl group as methanol); this route can thus potentially lead to rescue of the protein function. In eukarya, many Gproteins, such as Ras, have a carboxy terminal CAAX signal sequence that prompts a multistep modication to yield a C-terminal cysteine that is both methyl-esteried and S-isoprenylated; these modications target the protein towards membrane localization. Nitrogen methylation, be it on lysine, histidine or arginine, is likely to be irreversible. The alternation of methylation and acetylation of lysine residues in histones is involved in the regulation of eukaryotic gene expression, apparently by modication of proteinprotein interactions that impact chromatin structure (Rice and Allis,

S-Adenosylmethionine as Methyl Donor

Methylation is the most common route of consumption of S-adenosylmethionine, utilizing approximately 80% of the S-adenosylmethionine formed in mammals. S-Adenosylmethionine is the most widely used methylating agent in living creatures, acting as a modier of nucleic acids, proteins and a myriad of small molecules. Thus, Sadenosylmethionine (SAM) has the major role in onecarbon metabolism. The co-product of these reactions is Sadenosylhomocysteine (SAH), which is a potent inhibitor of most methylases. The intracellular SAM/SAH ratio is considered to be a regulator of the activity of these enzymes.

DNA and RNA methylation

Methyl transfer from S-adenosylmethionine to nucleic acids has important eects on DNA replication and transcription, and on RNA function. In bacteria, methylation of specic DNA sequences, either at the N6 position of adenine or the C5 of cytosine, is employed in restriction/ modication systems that are used to distinguish between host and foreign DNA. The importance of these systems is increasingly recognized in conjunction with appreciation of the extent of lateral gene transfer among microorganisms. Adenine methylation is also involved in regulation of cell division in some bacteria. In higher eukarya, methylation of cytosine in CpG islands is associated with transcriptional inactivity of specic genes, in processes that include tissue-specic gene expression, and in epigenetic phenomena such as hereditary imprinting and Xchromosome inactivation (Rice and Allis, 2001).
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S-Adenosylmethionine

ATP + L-Methionine

NH2

N H H3C H2 C H3+N O O H C H2 S+ CH2 H H OH OH O H H MTA N N

Ethylene Homoserine lactones

Methionine CH3 Proteins DNA, RNA Lipids and more SAH CO2 Decarboxylated SAM 5-Deoxyadenosyl radical Biotin, lipoic acid synthesis Ribonucleotide reductase DNA repair Lysine aminomutase

MTA

CH2CH2CH2NH3+ Polyamines
Figure 2 Illustrative 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.

2001). However, nitrogen methylation of proteins is more widespread, and its functions are typically unclear. One possibility is that trimethyllysine could provide a positive charge in a nonpolar environment, or a unique recognition site by binding to an aromatic amino acid pocket in a receptor through cation p interactions.

Miscellaneous methylations
A plethora of small molecule metabolites are formed from S-adenosylmethionine; a few examples are listed below. Methylation of most types of nucleophilic oxygen, sulfur, and nitrogen atoms is known, as well as of some not so obviously nucleophilic carbons. Among the most decorated compounds are tetrapyrolles such as the corrins and cofactor F(430). The electron transport cofactor ubiquinone (coenzyme Q) is dimethylated by S-adenosyl-

methionine. In mammals, substantial amounts of Sadenosylmethionine are used in methylation of guanidinoacetate to form the creatine used in energy storage. Biosynthetic methylation of amines includes the membrane constituent choline and the osmolyte betaine (N,N,N-trimethylglycine), as well as the neurotransmitter adrenaline (epinephrine). Glycine methylation in mammalian liver provides an indirect source of homocysteine to sustain cysteine synthesis. Other sulfonium ions such as Smethylmethionine (vitamin U) and the osmolyte dimethylsulfoniopropionate (DMSP) are fabricated through Sadenosylmethionine-dependent methylation of sulde precursors, although there may be alternative routes in some organisms. Methylation is common in the biosynthesis of secondary metabolites including polyketides and terpenes, and peptide antibiotics (e.g. cyclosporins). S-Adenosylmethionine-dependent methylation of many other atom types has been described. Methylation of halide
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ions by algae, fungi and plants leads to the volatile CH3Cl, CH3Br or CH3I. Methyl halides, in conjunction with the dimethyl sulde formed from DMSP, have signicant inuences on atmospheric ozone levels and acid rain formation. Methylation of heavy atoms mediates detoxication of toxic species, including selenides (R-Se-H), 2 22 telluride and tellurite (TeO2 3 ) and arsenic(III) (AsO3 ). These detoxication pathways have been reported throughout biological kingdoms. In addition, transfer of the S-adenosylmethionine methyl group to a Co 1 1 corrin activates the S-adenosylmethionine-dependent methionine synthase of E. coli.

complicated by circular permutations that, however, lead to similar three-dimensional topology. The protein structures are related to the Rossmann fold present in dinucleotidebinding proteins, which also recognize the adenosine moiety. A set of degenerate sequences that comprise a motif for Sadenosylmethionine-dependent methylases has been developed and has good predictive power for functional assignment of novel sequences (see Cheng and Blumenthal, 1999).

Polyamine Biosynthesis
The propylamine moiety of S-adenosylmethionine is used 1 in synthesis of the polyamines spermidine (NH3 (CH2)3 1 1 1 1 NH2 (CH2)4NH3 ) and spermine NH3 (CH2)3NH2 1 1 (CH2)4NH2 (CH2)3NH3 ). These abundant cations are 1 1 built upon putrescine (NH3 (CH2)4NH3 ), which is derived from ornithine or agmatine, and are widely distributed in nature (Tabor and Tabor, 1984). Although polyamines are involved in regulation of cellular proliferation, their relatively low anities for nucleic acids and other complexes reect ready dissociation, which has rendered their exact molecular function elusive. In this pathway S-adenosylmethionine is initially decarboxylated to generate the donor of the propylamine group used in the synthesis of the spermidine from putrescine, and then of spermine from spermidine. The 5-methylthioadenosine formed in polyamine synthesis is recycled in some organisms into adenine and methionine through a complex set of reactions that are not uniformly well characterized; adenine can be liberated by hydrolases or phosphorylases, and the corresponding 5-methylthioribose (or 5methylthioribose 1-phosphate) is converted in a multistep path to methionine. This salvage pathway is integral to the conservation of reduced sulfur. S-Adenosylmethionine decarboxylase is an unusual enzyme that employs a conserved covalently attached pyruvoyl group to form a Schi base with the substrate as catalytic intermediate. This cofactor contrasts with the pyridoxal phosphate more commonly used as electron sink by amino acid decarboxylases (Hackert and Pegg, 1997). SAdenosylmethionine decarboxylase is synthesized as a precursor protein that self-catalyses cleavage at an internal serine residue to form two polypeptides; the chain derived from the carboxyl terminal region of the precursor has a pyruvoyl group, derived from the serine, at the N-terminus. This internal cleavage reaction proceeds through an ester intermediate and is in part analogous to intein processing. It is remarkable that use of a rare pyruvoyl group cofactor is maintained in S-adenosylmethionine decarboxylases across evolution, whereas the remainder of the enzyme sequence is widely divergent among dierent kingdoms. S-Adenosylmethionine decarboxylase remains the only eukaryotic protein known to have a pyruvoyl cofactor. The structure of the human enzyme (PDB code 1jen) has a topology that is unique among known protein structures; it is not related to

Biochemistry of methylation
The majority of mechanistic studies of transfer of alkyl group from S-adenosylmethionine have involved methylation. Early studies showed that methyl transfer from Sadenosylmethionine to homocysteine has a more favourable enthalpy change than methyl transfer from DMSP or (CH3)3S 1 (Mudd, 1973). These data conrmed the highenergy status of S-adenosylmethionine; the dierences among the sulfonium compounds were attributed to variations in aqueous solvation energies of the sulfonium/sulde pairs, perhaps related to the greater conformational exibility and larger surface areas for hydration of SAM/SAH versus (CH3)3S 1 /(CH3)2S. Experiments using chiral methyl groups (CHDT, or C 1H2H3H) showed that several enzyme-catalysed methylation reactions proceed with inversion of stereochemical conguration at the methyl carbon. The stereochemical result is consistent with a single displacement reaction wherein the methyl group is directly transferred from Sadenosylmethionine to the substrate without the intervention of chemical intermediates (Floss and Tsai, 1979). Kinetic isotope eects of the methyl transfer catalysed by catechol O-methyltransferase demonstrated a SN2-type reaction, concordant with stereochemical data (Hegazi et al., 1979). Thus, the available results indicate that alkyl group transfer from S-adenosylmethionine occurs by direct attack of a substrate nucleophile on an electrondecient carbon, suggesting that important roles in catalysis are proximity of the reactant and its orientation within the active site, in conjunction with a basic group, if needed, to activate the nucleophile. Protein crystallographic studies have shown that methylases are composed of a functionally conserved catalytic domain and a distinct specicity determination domain (Cheng and Blumenthal, 1999). DNA methylases were the rst enzymes found to ip the target nucleotide base out of the double helix in order to expose their substrate, a mode of action that has become increasingly appreciated (Cheng and Roberts, 2001). The catalytic domain is conserved in structure, although the sequence conservation can be low; identication of methylases based on linear sequence alone is
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S-Adenosylmethionine

the structures of the pyruvoyl-containing histidine decarboxylase or aspartate decarboxylase. Decarboxylated S-adenosylmethionine appears not to be a substrate for methylases, and is committed to action as a propylamine donor. Propylamine transfers to putrescine and spermidine are commonly catalysed by dierent proteins. Crystallographic studies show that the spermidine synthase (putrescine aminopropyltransferase) from Thermotoga maritima has a fold similar to the catalytic domain of many methylases, consistent with the analogous function of transfer of an alkyl group from the sulfonium centre to a nucleophile (PDB code 1inl).

Radical S-Adenosylmethionine
The discovery that 5-deoxyadenosyl free radicals are formed by C5-S bond cleavage of S-adenosylmethionine in some enzymatic reactions has led to an even broader appreciation of the diversity of its biological roles (Frey and Booker, 2001). In some radical reactions, S-adenosylmethionine acts as a free-radical-carrying cofactor, analogous to the function long thought to be reserved for coenzyme B12. In other reactions, S-adenosylmethionine is consumed, thus acting as a substrate. Radical formation from S-adenosylmethionine is a challenging task since the CS bond is quite strong, approximately twice as strong as the CCo bond in cobalamins. The proteins involved in these reactions each contain ironsulfur centres, and it appears likely that electron transfer from the centre to the S-adenosylmethionine is a step in radical formation. A study of sequence databases has implicated the existence of several hundred proteins that are likely to be involved in these types of reactions (Soa et al., 2001). The paradigm for participation of S-adenosylmethionine as a cofactor in rearrangements is clostridial lysine 2,3-aminomutase, a pyridoxal phosphate-containing enzyme that catalyses conversion of the common a-lysine to b-lysine (Frey and Booker, 2001). In this reaction, Sadenosylmethionine is converted to a 5-deoxyadenosyl radical and methionine via one-electron transfer from a four ironsulfur centre in the 1 1 state, [4Fe-4s] 1 1. Subsequently the 5-deoxyadenosyl radical abstracts a hydrogen atom from the substrate, the substrate radical rearranges to the product radical, then the electron ow reverses to yield product and regenerate S-adenosylmethionine. Reversible formation of a 5-deoxyadenosyl radical from S-adenosylmethionine has been implicated in a newly recognized means of repair of thymidine dimers in damaged DNA; a Bacillus subtilis SP photolyase catalyses the cleavage of the carboncarbon bonds of the thymidine dimer, using S-adenosylmethionine but not the light energy that most photolyases require. In reactions catalysed by other radical S-adenosylmethionine enzymes, S-adenosylmethionine is converted on a stoichiometric basis to 5-deoxyadenosine and methionine. The anaerobic ribonucleotide reductase and pyruvate formate lyase from E. coli contain a glycyl radical; formation of this radical is catalysed by a specic activating enzyme (a subunit of the holoenzyme in the former case) that uses S-adenosylmethionine and an iron sulfur centre. In these reactions, the glycyl radical is formed on the a-carbon via hydrogen atom abstraction and Sadenosylmethionine is stoichiometrically consumed with incorporation of the abstracted hydrogen into 5-deoxyadenosine. The glycyl radical is a precursor for cysteinederived thiyl radicals that react with the substrate during catalysis. S-Adenosylmethionine is also involved in the insertion of sulfur into unactivated CH bonds in the biosynthesis of
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5-Deoxyadenosyl Group Transfer

Up to the year 2002, reports of alkylation of nucleophiles by the 5-deoxyadenosyl group of S-adenosylmethionine were notably absent from the literature. This gap was lled by report of a bacterial enzyme that catalysed the reaction of uoride ion with S-adenosylmethionine to 5-uorodeoxyadenosine (OHagan et al., 2002). This bacterial source could also convert 5-uorodeoxyadenosine to uoroacetate. By analogy, this series of reactions probably yields the toxin uoroacetate produced by numerous plant species.

Other Alkylations by S-Adenosylmethionine

The methionyl side-chain of S-adenosylmethionine is cyclized to 1-amino-1-carboxycyclopropane, which is a precursor of the plant hormone ethylene. The hypermodied nucleoside base queuosine, found in tRNA, incorporates the ribose of S-adenosylmethionine into an epoxycyclopentane-modied 7-deazaguanine. Alkylation by the intact carboxylaminopropyl group of S-adenosylmethionine is used in the biosynthesis of selective tRNA bases, as well as the hypermodied histidine residue diphthamide (2-[3-carboxyamido-3-(trimethylammonio)propyl]histidine) in the protein elongation factor 2, and in biosynthesis of secondary metabolites such as the norcardicin b-lactam antibiotics. The modied amino acid hypusine (Ne-(4-amino-2-hydroxybutyl)lysine), present exclusively in protein elongation factor 5A of eukarya and archaea, is formed indirectly from S-adenosylmethionine through incorporation of the butylamine moiety from spermidine. Cyclopropane fatty acids are present in the lipid membranes of many bacteria and some eukaryotes, for reasons perhaps related to membrane uidity. These three-membered rings are formed by addition of the methyl group of S-adenosylmethionine to the double bond of a cisunsaturated fatty acyl chain, followed by rearrangement in a mechanism that is still unclear.

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S-Adenosylmethionine

lipoic acid and biotin. Both 5-deoxyadenosyl and substrate radicals are intermediates. The formation of CS bonds is stoichiometric with S-adenosylmethionine consumption, and hydrogens from the substrate are incorporated into the 5-deoxyadenosine produced. The source of the sulfur that is incorporated into the product is less clear and may arise from sulde present in an ironsulfur cluster.

S-Adenosylmethionine in Signalling
S-Adenosylmethionine is a precursor to the acylhomoserine lactones that are secreted and sensed by Gram-negative bacteria as a means of assessing cell density, a process known as quorum sensing (Schauder and Bassler, 2001). These species-specic compounds, also known as autoinducers, allow bacteria to determine the density of their colleagues and to moderate gene expression accordingly. For example, Vibrio species use acylhomoserine lactones to regulate the energetically costly process of light production, whereas Pseudomonads use this method to determine when to form biolms. Dierent organisms produce (and sense) compounds with dierent acyl groups (obtained from acyl carrier protein), and thus species-specic signalling can be obtained. The reaction sequence proceeds through acylation of the amino group of the methionyl portion of S-adenosylmethionine, followed by cyclization of the side-chain with displacement of 5-methylthioadenosine. In a related signalling process, the ribosyl group of S-adenosylmethionine serves as a precursor to a novel boron-containing quorum-sensing molecule that is produced and detected by many bacterial species, allowing dierent types of organisms to communicate with one another.

and sulfur metabolism; thus it is not surprising that it is employed as a regulatory molecule. It has a transcriptional regulation role for methionine biosynthetic genes that has been characterized genetically and biochemically in yeast and enteric bacteria. The S-adenosylmethionine-binding MetJ repressor protein of E. coli has a three-dimensional topology that is unique among known protein structures (PDB code 1cmc). As examples of more direct control of metabolism, S-adenosylmethionine acts as an allosteric regulator of the eukaryotic cysteine biosynthetic enzyme cystathionine b-synthase, and the plant threonine synthase.

Medical Aspects
Humans synthesize approximately 7 grams of S-adenosylmethionine per day, primarily in the liver. Formation of S-adenosylmethionine formation is a major pathway in the metabolism of dietary methionine, an essential amino acid in mammals. S-adenosylmethionine is an integral component of the sulfur cycle since the S-adenosylhomocysteine formed in methylation reactions is converted to homocysteine (and adenine), which leads to cystathionine and then to cysteine and glutathione. Many tumour cells require methionine for growth, a property that appears to be related to impaired metabolism of S-adenosylmethionine. Dysfunctional S-adenosylmethionine metabolism is also common in diseased livers. Reduced biosynthesis of Sadenosylmethionine resulting from hereditary mutations in a synthetase coding gene has been found in patients with isolated, persistent hypermethioninaemia, generally diagnosed during routine neonatal screening for homocystinuria. These patients are nonsymptomatic, with the exception of bad breath due to exhalation of dimethyl sulde. Inhibitors of S-adenosylmethionine decarboxylase have been investigated clinically in the contexts of anticancer and antiparasitic therapies.

The Other Roles of SAdenosylmethionine

S-Adenosylmethionine is employed as an amino donor in transamination reactions in the synthesis of the biotin component 7,8-diaminopelargonic acid, for reasons that remain elusive. The a-amino group of S-adenosylmethionine has an unusually low pKa of 7.8, compared to 9.2 for methionine, apparently due to the proximity of the sulfonium cation. Whether the relative ease of deprotonation is important in biological processes is unclear. The pKa of the S-adenosylmethionine carboxylate group is also slightly reduced, to 1.8 compared to a more typical value 2.2 for methionine.

S-Adenosylmethionine as a nutriceutical
S-Adenosylmethionine is now utilized in popular treatments of human disorders. It has been reported to have abilities to ameliorate diverse maladies such as arthritis, liver cirrhosis and depression. The receptors and/or transport systems that mediate these phenomena are yet uncharacterized. Although the molecular bases of these eects are still unclear, S-adenosylmethionine has come from the laboratory to the supermarket. What a long strange trip it has been.

S-Adenosylmethionine as regulator
S-Adenosylmethionine is a branch point intermediate in the pivotal metabolic pathways of amino acid, nucleotide
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References
Cantoni GL (1953) S-Adenosylmethionine: a new intermediate formed enzymatically from l -methionine and adenosine triphosphate. Journal of Biological Chemistry 204: 403446.

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Cheng X and Blumenthal RM (1999) S-Adenosylmethionine-dependent Methyltransferases: Structures and Functions. Singapore: World Scientic. Cheng X and Roberts RJ (2001) AdoMet-dependent methylation, DNA methyltransferases and base ipping. Nucleic Acids Research 29: 37843795. Choi JY, Lee TW, Jeon KW and Ahn TI (1997) Evidence for symbiontinduced alteration of a hosts gene expression: irreversible loss of SAM synthetase from Amoeba proteus. Journal of Eukaryotic Microbiology 44(5): 412419. Clarke S (1993) Protein methylation. Current Opinion in Cell Biology 5: 977983. Floss HG and Tsai MD (1979) Chiral methyl groups. Advances in Enzymology and Related Areas of Molecular Biology 50: 243302. 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) Identication 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, vol. 2, pp. 210 216. New York: Academic Press. Hegazi MF, Borchardt RT and Schowen RL (1979) a-Deuterium and carbon-13 isotope eects for methyl transfer catalyzed by catechol-Omethyl-transferase. SN2-like transition state. Journal of the American Chemical Society 101: 43594365. Mudd SH (1973) The adenosyltransferases. In: Boyer PD (ed.) The Enzymes, 3rd edn, vol. 8, pp. 121154. New York: Academic Press. OHagan D, Scharath C, Cobb CL, Hamilton JT and Murphy CD (2002) Biosynthesis of an organouorine 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(3): 263273. Schauder S and Bassler BL (2001) The languages of bacteria. Genes and Development 15: 14681480. Soa HJ, Chen G, Hetzler BG, Reyes-Spindola JF and Miller NE (2001) Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional

characterization using new analysis and information visualization methods. Nucleic Acids Research 29: 10971106. Tabor C 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: 135139.

Further Reading
Borchardt RT, Creveling CR and Ueland PM (1986) Biological Methylation and Drug Design: Experimental and Clinical Role of SAdenosylmethionine (Experimental Biology and Medicine). Clifton NJ: Humana Press. Brown R, Colman C and Bottiglieri T (2000) Stop Depression Now: SamE: The Breakthrough Supplement That Works as Well as Prescription Drugs, in Half the Time_with No Side Eects. New York: Berkley Publishing Group. Chiang PK, Gordon RK, Tal J et al. (1996) S-Adenosylmethionine and methylation. FASEB Journal 10: 471480. 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: 429441. Online Mendelian Inheritance in Man (OMIM) (2000) Methionine adenosyltransferase deciency. MIM Number: 250850: 10/26/2000. Johns Hopkins University, Baltimore, MD. http://www.ncbi.nlm.nih.gov/omim Ravanel S, Gakiere B, Job D and Douce R (1998) The specic features of methionine biosynthesis and metabolism in plants. Proceedings of the National Academy of Sciences of the USA 95: 78057812. Sekowska A, Kung HF and Danchin A (2000) Sulfur metabolism in Escherichia coli and related bacteria: facts and ction. Journal of Molecular Microbiology and Biotechnology 2: 145177. Thomas D and Surdin-Kerjan Y (1997) Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews 61: 503532.

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