S-adenosylmethionine SAM

A naturally occuning sulfonium salt, S-adenosylmethionine (SAM), is a key substance in certain biological processes. It is fonned by a nucleophilic substitution in which the sulfur atom of methionine attacks the primary car bon of adenosine triphosphate, displacing the triphosphate leaving group as shown in Figure 16.7. 

FIGURE 16.7 Nucleophilic substitution at the primary carbon of adenosine triphosphate (ATP) by the sulfur atom of methionine yields S-adenosylmethionine (SAM). The reaction is catalyzed by an enzyme. 

The farnesylation and subsequent processing of the Ras protein. Following farnesylation by the FTase, the carboxy-terminal VLS peptide is removed by a prenyl protein-specific endoprotease (PPSEP) in the ER, and then a prenylprotein-specific methyltransferase (PPSMT) donates a methyl group from S-adenosylmethionine (SAM) to the carboxy-terminal S-farnesylated cysteine. Einally, palmitates are added to cysteine residues near the C-terminus of the protein. 

S-(5 -Deoxyadenosin-5 -yl)-L-methionine (AdoMet) S-[(1-Adenin-9-yl)-1,5-dideoxy-p-D-ribofuranos-5-yl]-L-methionine [trivial name S-adenosylmethionine (SAM)]... 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

Many NRPs such as cyclosporin, complestatin, actinomycin, and chondramide contain N-methyl amides. M-Methyl transferase (N-MT) domains utilize S-adenosylmethionine (SAM) as a cofactor to catalyze the transfer of the methyl group from SAM to the a-amine of an aminoacyl-S-PCP substrate. The presence of M-methylamides in NRPs is believed to protect the peptide from proteolysis. Interestingly, N-MT domains are incorporated into the A domains of C-A-MT-PCP modules, between two of the core motifs (A8 and A9). MT domains contain three sequence motifs important for catalysis. ° 0-Methyl transferase domains are also found in NRPSs and likewise use the SAM cofactor. For instance, cryptophycin and anabaenopeptilide synthetases contain 0-MT domains for the methylation of tyrosine side chains. These 0-MT domains lack one of the three core motifs described for N-MT domains. ... 

Methionine, another sulfur-containing amino acid, is part of S-adenosylmethionine (SAM), a methyl donor in biochemical pathways. 

In biological methylation, the 5-methyl group of the amino acid L-methionine is used to methylate suitable O, N, S, and C nucleophiles. First, methionine is converted into the methylating agent S-adenosylmethionine (SAM). SAM is nucleoside derivative (see Section 14.3). Both the formation of SAM and the subsequent methylation reactions are nice examples of biological Sn2 reactions. 

Now we have seen that the usual reagent for biological methylations is S-adenosylmethionine (SAM) (see Box 6.4). One occasion where SAM is not employed, for fairly obvious reasons, is the regeneration of methionine from homocysteine, after a SAM methylation. For this, A -methyl-FH4 is the methyl donor, with vitamin B12 (see Box 11.4) also playing a role as coenzyme. 

Histone methylation participates in the regulation of gene expression patterns. Unlike histone acetylation, histone methylation does not alter the charge of the amino acid and hence the histone tail. There are changes in the basicity and the hydrophobicity which are relatively small when viewed at the scale of the histone but still influence the affinity of the histone tails to certain proteins, for example transcription factors, which in turn result in certain signaling events. The histone methyltransferases are usually subdivided into three classes SET domain lysine methyltransfeases, nonSET domain lysine methyltransferases and arginine methyltransferases (PRMTs). All of them utilize S-adenosylmethionine (SAM) as cosubstrate for the methylation reaction... 

Transfer of adenosine from ATP to the sulfur of the essential amino acid Met produces S-adenosylmethionine (SAM). 

This type of alkylation also occurs in nature. For example, S-adenosylmethionine (SAM), an important biological methylation reagent, is involved in the biosynthesis of the antibiotic indolmycin and is responsible for the enantioselective C-methylation of an a-oxocarboxylic acid arising from tryptophan3. 

Methionine is one of four amino acids that form succinyl CoA. This sulfur-containing amino acid deserves special attention because it is converted to S-adenosylmethionine (SAM), the major methyl-group donor in one-carbon metabolism (Figure 20.8). Methionine is also the source of homocysteine—a metabolite associated with atherosclerotic vascular disease. 

Methionine is the major precursor in the biochemical pathway to ethylene (9). Ethylene is formed from carbons 3 and 4 of methionine which is degraded in reactions possibly involving free radicals and oxygen (9). Recently Adams and Yang (10,11) identified S-adenosylmethionine (SAM) and 1-aminocyclopropane-l-carboxylic acid (ACC) as intermediates in the pathway from methionine to ethylene. The sequence of reactions in the pathway... 

Phase II methylation occurs with the S-adenosylmethionine (SAM) cofactor acting as a methylating agent ... 

Homocysteine is formed as an intermediary amino acid in the methionine cycle (Fig. I). Methionine is metabolized to s-adenosylmethionine (SAM), the methyl donor in most methylation reactions and essential for the synthesis of creatinine, DNA, RNA, proteins, and phospholipids. SAM is converted by methyl donation to s-adenosylhomocysteine (SAH), which is then hydrolyzed to homocysteine. SAH is an inhibitor of methyl group donation from SAM. 

The major (salvage) pathways for the formation of phosphatidylcholine and ethanolamine are illustrated in Figure 19.16. Free (dietary) choline and etha-nolamine are converted to their CDP derivatives, which then react with diacyl-glycerol to form phosphatidylcholine and ethanolamine. In the lungs, another pathway forms dipalmitoyl phosphatidylcholine, a powerful surfactant. Phos-phatidylethanolamine may be methylated by S-adenosylmethionine (SAM see Chapter 20) to yield phosphatidylcholine. The reaction is catalyzed by two enzymes the first methyl group is transferred via phosphatidylethanolamine N-methyltransferase I. The other two methyl groups are transferred by phosphatidylethanolamine N-methyltransferase II. Some authorities believe that the two enzymes are identical. It has also been proposed that methylation of phospha-... 

A number of proteins such as histones, cytochrome c and certain flagellar proteins are found to contain methylated amino acids (19). Three different methylases have been characterized and all require S-adenosylmethionine (SAM) as the methyl donor (20-23). Protein methylase I (SAM-protein arginine methyl transferase) methylates the guanidine side chain of arginine residue protein methylase II (SAM-protein carboxyl methyltransferase) transfers methyl groups only to 8- and y-carboxyl groups in the peptide chain. Carboxyl groups in the a position cannot serve as acceptors. Protein methylase III (SAM-protein lysine... 

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