SAM- dependent methylation

Histone methylation is a common posttranslational modification fond in histones. Histone methylations have been identified on lysine and arginine residues. In case of lysines S-adenosyl-methionine (SAM) dependent methyl transferases catalyze the transfer of one, two or three methyl groups. Lysine methylation is reversible and lysine specific demethylases have been... 

SAM-dependent methylation of salicylic acid. The salicyl alcohol derivative salicin, found in many species of willow (Salix species Salicaceae), is not derived from salicylic acid, but probably via glucosylation of salicylaldehyde and then reduction of the carbonyl (Figure 4.27). Salicin is responsible for the analgesic and antipyretic effects of willow barks, widely used for centuries, and the template for synthesis of acetylsalicylic acid (aspirin) (Figure 4.27) as a more effective analogue. 

The most widely used methyl donor for enzymatic methyl transfer is the cofactor S-adenosyl-L-methionine (SAM). The methyl moiety on the L-methionine is supplied by another known methyl donor, N5-methyl tetrahydrofolate.30 To date, numerous enzymes that perform SAM- dependent methylation reactions have been described in plants, and several reports attempting to sort out their evolutionary relationships have been published.31- 3... 

The non-phenolic furofuran lignan, (-l-)-eudesmin, from Magnolia kobus var. borealis is formed from pinoresinol by two SAM-dependent methylation steps (Miyauchi and Ozawa, 1998). Cell-free extracts catalysed the successive non-stereospecific methylation both of (-1-)- and (—)-pinoresinol. Thus, the stereospecificity has to be established in an earlier step. 

Cobalamin-dependent methionine synthase contains a built-in repair mechanism. If accidental oxidation of cob(I)alamin leads to inactive cob(lI)alamin, then the enzyme employs SAM and reduced flavodoxin to regenerate cob(I)alamin. Although the redox equilibrium below lies mainly on the left side, any cob(l)alamin formed is trapped by SAM-dependent methylation to yield methylcobalamin. 

S-adenosyl-L-methionine (SAM)-dependent methyl-ation was briefly discussed under Thiomethylation (see Figure 14). Other functional groups that are methylated by this mechanism include aliphatic and aromatic amines, N-heterocyclics, monophenols, and polyphenols. The most important enzymes involved in these methylation reactions with xenobiotics are catechol O-methyltransferase, histamine N-methylt-ransferase, and indolethylamine N-methyltransferase - each catalyzes the transfer of a methyl group from SAM to phenolic or amine substrates (O- and N-methyltransferases, respectively). Methylation is not a quantitatively important metabolic pathway for xenobiotics, but it is an important pathway in the intermediary metabolism of both N- and O-contain-ing catechol and amine endobiotics. 

Methylation is the addition of a carbon atom to a molecule, usually causing a change in the function of the methylated molecule. For example, methylation of the neurotransmitter dopamine by catechol-O-methyltransferase renders it inactive. With only two exceptions, 5-adenosylmethionine (SAM), an activated form of the essential amino acid methionine, is the methyl donor for each of the more than 150 methylation reactions, which regulate a large number of cellular functions. One exception is methylation of homocysteine (HCY) to methionine by the cobalamin (vitamin Bi2)-dependent enzyme methionine synthase, which utilizes 5-methyltetrahydrofolate (methylfolate) as the methyl donor, serving to complete the methionine cycle of methylation, as illustrated in Fig. 1 (lower right). Notably, HCY formation from S-adenosylhomocysteine (SAH) is reversible and, as a result, any decrease in methionine synthase activity will be reflected as an increase in both HCY and SAH. This is significant because SAH interferes with SAM-dependent methylation reactions, and a decrease in methionine synthase activity will decrease all of these reactions. Clearly methionine synthase exerts a powerful influence over cell function via its control over methylation. 

In summary, folate is a vitamin acquired from the diet that is essential for 1-carbon metabolism. Inadequate folate levels inhibit DNA synthesis by limiting purine nucleotide and dTMP levels, which results in the abnormal cellular proliferation observed in megaloblastic anemia. Folate is also required to replenish the methionine pool for SAM-dependent methylation reactions. 

As observed in the section discussing BtrN and DesII, radical SAM enzymes have already been shown to play a critical role in the synthesis of certain elements of antibiotic compounds. Moreover, we observed in the MiaB section that a radical SAM enzyme is responsible for catalyzing a methylation reaction in the synthesis of ms i A. Methyl transfer reactions in biology commonly utilize DNA methylase enzymes or SAM-dependent methyltransferases the latter system has been touched upon in the multiple SAM-dependent methyl transfer reactions involved in yW synthesis. However, a unique methylation reaction has recently been proposed that invokes the use of both SAM and methylcobalamin. 

An example of (V-methylation in presence of SAM as the methyl group donor is provided by the caffeine biosynthetic pathway involving three SAM-dependent methylation steps (Figure 1.6) [5]. The methylation reactions are catalyzed by (V-methyltransferases (CaXMTl, CaMXMTl, and CaDXMTl), which, respectively, convert xanthosine into 7-methylxanthosine, 7-methylxanthine into... 

Transmethylation reactions are widely used in modification of a variety of biomolecules such as nucleic acids, proteins, phospholipids, and bioamines. In these reactions, SAM serves as the universal methyl donor (Mato et al. 1997). Methylation reactions yield the common product 5-adenosyl-L-homocysteine (SAH), and most SAM-dependent methylations are strongly inhibited by accumulation of SAH (Mato... 

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