5-Adenosyl-methionine

Methionine (Met or M) ((5)-2-amino-4-(methylsulfanyl)-butanoic acid) is a nonpolar, neutral, amino acid with the formula HOOCCH(NH2)CH2CH2SCH3. Together with Cys, Met is one of the two sulfur-containing proteinogenic amino acids and a great antioxidant. Its derivative 5-adenosyl methionine (SAM) serves as a methyl donor. ... 

This enzyme [EC 2.5.1.6], also known as 5 -adenosyl-methionine synthetase, catalyzes the reaction of ATP... 

For the first time, an enzyme able to create a carbon-fluorine bond has been isolated from Streptomyces cattleya. This enzyme has been characterized and then named fluorinase. In the presence of fluoride ions, this enzyme catalyzes the conversion of 5-adenosyl methionine into 5 -fluoro-5 desoxyadenosine (Figure 4.3). ... 

Transfer of the methyl group from 5,-adenosylmethi-onine to an acceptor yields S -adenosylhomocysteine (Fig. 18-18, step (2)), which is subsequently broken down to homocysteine and adenosine (step (3)). Methionine is regenerated by transfer of a methyl group to homocysteine in a reaction catalyzed by methionine synthase (step (4)), and methionine is reconverted to 5-adenosyl-methionine to complete an activated-methyl cycle. 

The methyl-branch is introduced at the C-3 position of tautomer 11 of the keton 9 by an electrophilic.attack with active methione (S-methyl-5 -adenosyl methionine). Thus the 2,6-dideoxy-4-keto-3-C-methyl-D-ery//iro glycoside 12 results which after reduction furnishes, e.g., D-mycarose (cf. also Ref. [5]). 

Phosphatidylserine arises by an exchange of the ethanolamine residue of phosphatidylethanolamine for a seryl group. Decarboxylation of the serine of phosphatidylserine reforms phosphatidylethanolamine. Three successive methylation reactions convert phosphatidylethanolamine to phosphatidylcholine. 5-Adenosyl-methionine is the methyl-group donor (Chap. 15) (see Fig. 13-14). 

A DNA modification which changes gene transcription is methylation of nucleotide bases. Heterochromatin contains heavily methylated DNA which cannot be transcribed. Genes in euchromatin are less methylated and are transcribable. Methylation at C5 of cytosine in CpG sequences by a methyltransferase, with 5-adenosyl methionine (SAM) as methyl donor, silences genes in heterochromatin. Methylation may affect the higher-order structure of DNA and may impede access of the transcriptional machinery to DNA. Members of the histone Hj family have been associated with transcriptional repression, because these histones bind preferentially to methylated CpG sequences (Fig. 9.10).4i... 

During polyamine and ethylene biosynthesis, 5 -adenosyl-methionine (AdoMet) is converted to methylthioadenosine. 

Another structural feature often found in NRPS products is N-methylated amide bonds. The domain that introduces this Ci unit, the so-called methyltransferase (Mt) domain, is situated between the A and the PCP domain (21). By consumption of 5-Adenosyl-methionine, the a-amino group of the acceptor substrate is methylated before condensation with the donor. 

Figure 1 P. aeruginosa QS system. Its mechanism, (a) Biosynthesis of acyl-homoserine lactone (AHL). Abbreviations SAM, 5-adenosyl methionine ACP, acyl carrier protein, (b) General chemical structure of AHL molecules, generally called autoinducer-1 (AI-1). (c) Chemical structure of V. fischeri AI-1. (d) Chemical structure of P. aeruginosa 3-oxo-C y-HSL and (e) C4-HSL. (f) Pseuodomonas quinolone signal, PQS.

Adenosyl methionine is most widely used for depressive disorders, and about 40 clinical trials have been carried out. A recent meta-analysis concluded that at 200-1600 mg/day it was superior to placebo, and with a global effect size ranging from 17%i to 38%i, it was as effective as tricyclic antidepressants. A later meta-analysis reported on 16 open uncontrolled trials, 13... 

A methyl group, when grafted on a nitrogen or sulfur atom, can transform this latter in an onium, able to act as methyl donor. In living organisms the usual suppliers of methyl rests are choline and methionine. Methionine is first activated in vivo by combination with adenosine to yield 5-adenosyl-methionine (SAM Figure 20.8). 

Apart from 24-methylene cycloartanol (2-F) and cyclolaudenol (2-G), which in maize and barley embryos could give rise to 24a- and 24 -methyl sterols respectively, a further primary product of methylation, cyclosadol (2-T) has recently been foimd in maize and barley embryos. Its significance in the major pathway of sterol synthesis is still under investigation, but minor components such as 4-T and 8-T have also been reported in maize. The overall pattern of the type of compounds formed by the first attack of 5-adenosyl methionine on cycloartenol is outlined in Fig. 7. 

Additional V-methyl and 0-methyl groups frequently encountered in steroid alkaloids appear to arise conventionally from 5-adenosyl methionine. 

One subunit of the capping enzyme removes the y phosphate from the 5 end of the nascent RNA emerging from the surface of an RNA polymerase II. Another domain of this subunit transfers the GMP moiety from GTP to the 5 -diphosphate of the nascent transcript, creating the unusual guanosine 5 -5 -triphosphate structure. In the final steps, separate enzymes transfer methyl groups from 5-adenosyl-methionine to the N/ position of the guanine and the 2 oxygens of riboses at the 5 end of the nascent RNA. 

Many similar reactions are brought about by alkylating agents normally present in cells, such as 5-adenosyl-methionine. 

An early key intermediate in benzylisoquinoline biosynthesis is (57), which by decarboxylation affords (59) this in turn leads to (61) and on to alkaloids (Scheme 2). Confirmation of this pathway has come from a study using cell-free preparations of P. somniferum stems and seed capsules. It was found that this preparation catalysed the formation of (57), (59), and (61) from dopamine (54) plus 3,4-dihydroxyphenylpyruvic acid (55) without the addition of 5-adenosyl-methionine, NADPH, and pyridoxal phosphate, the reaction stopped at (57). The formation of the alkaloids reticuline, thebaine, codeine, and morphine, produced by whole plants, could not be detected with this cell-free system. The results confirm not only the intermediacy of (57) and (59) in benzylisoquinoline biosynthesis, but also the involvement of (54) and (55). 

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