IS-adenosylmethionine

Frey, P. A., 1993, Lysine 2,3-aminomutase is adenosylmethionine a poor manis adenosylcobalamin FASEB J. 7 662n670. 

The decomposition of iS-adenosylmethionine (CXIX) at pH 4 or in neutral solution gives nearly quantitative yields of methylthioadenosine... 

Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible most reduced—methyl intermediate—methylene and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is -adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. -Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle. 

Radioenzymatic methods had also been used to quantify urinary NM." " Phenyletha-noleamine-A -rnethyltransferase and H iS -adenosylmethionine convert NM to its [ H]N-methylated derivative, The main advantages of this method were its high... 

Methionine is converted to iS-adenosylmethionine (SAM), which donates its methyl group to other compounds to form S-adenosylhomocysteine (SAH). SAH is then converted to homocysteine (Fig. 39.14). Methionine can be regenerated from homocysteine by a reaction requiring both FH4 and vitamin B12 (a topic that is considered in more detail in Chapter 40). Alternatively, by reactions requiring PLP, homocysteine can provide the sulfur required for the synthesis of cysteine (see Fig. 39.7). Carbons of homocysteine are then metabolized to a-ketobutyrate, which undergoes oxidative decarboxylation to propionyl-CoA. The propionyl-CoA is then converted to snccinyl CoA (see Fig. 39.14). 

This enzyme catalyses the reaction that generates methionine from homocysteine, a metabolic step associated with transmethylation by iS-adenosylmethionine. 

The product, iS-adenosylmethionine, is capable of donating its methyl group to suitable acceptors with neutralization of the sulfonium charge. It has also been shown that iS-adenosylmethionine can be decarboxylated by an enz3one in E. coli to form enzymically condensed with putrescine to form spermidine [Eq. (89)] 361). Thiomethyladeno ne is, presumably, the other product. 

Although only limited results are currently available, enzymes associated with amino acid biosynthesis in higher plants appear to be nuclear encoded. Consequently, transport into chloroplasts would be expected to be facilitated by the presence of an N-terminal transit peptide on the initial translation product. This appears to be the case with acetolactate synthase (19), which is nuclear encoded and localized in chloroplasts (Chaleff and Ray, 1984). Evidence for nucleotide sequences that could code for an N-terminal transit peptide composed of between 85 and 99 residues was obtained for the genes isolated from Arabidopsis and Nicotiana (Mazur et al, 1987). The absence of synthesis of iS-adenosylmethionine in plastids is further supported by the apparent lack of a nucleotide sequence coding for a transit peptide in an adenylatetransferase Arabidopsis gene (Peleman et al., 1989). 

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. 

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

The most common example of this process in living organisms is the reaction of the amino acid methionine with adenosine triphosphate (ATP Section 5.8) to give S-adenosylmethionine. The reaction is somewhat unusual in that the biological leaving group in this SN2 process is the triphosphate ion rather than the more frequently seen rliphosphate ion (Section 11.6). 

Posttranslational modification of preformed polynucleotides can generate additional bases such as pseudouridine, in which D-ribose is linked to C-5 of uracil by a carbon-to-carbon bond rather than by a P-N-glycosidic bond. The nucleotide pseudouridylic acid T arises by rearrangement of UMP of a preformed tRNA. Similarly, methylation by S-adenosylmethionine of a UMP of preformed tRNA forms TMP (thymidine monophosphate), which contains ribose rather than de-oxyribose. 

When acting as a methyl donor, 5-adenosylmethionine forms homocysteine, which may be remethylated by methyltetrahydrofolate catalyzed by methionine synthase, a vitamin Bj2-dependent enzyme (Figure 45-14). The reduction of methylene-tetrahydrofolate to methyltetrahydrofolate is irreversible, and since the major source of tetrahydrofolate for tissues is methyl-tetrahydrofolate, the role of methionine synthase is vital and provides a link between the functions of folate and vitamin B,2. Impairment of methionine synthase in Bj2 deficiency results in the accumulation of methyl-tetrahydrofolate—the folate trap. There is therefore functional deficiency of folate secondary to the deficiency of vitamin B,2. 

Despite our earlier failure in formate feeding experiments, [3- C]serine, [1,2- CJglycine, and [Me- C]methionine were found to enrich C-13 in neosaxitoxin effectively (7). The best incorporation was observed with methionine, indicating it is the direct precursor via S-adenosylmethionine. Glycine C-2 and serine C-3 must have been incorporated through tetrahydrofolate system as methyl donors in methionine biosynthesis. 

S-adenosylmethionine carboxylase is the source of the propylamine in the polyamines spermine and spermidine. The activity of spermine synthase introduces this into spermidine and spermine, which has already been noted. It is worth pointing out that, whereas the inducible histidine decarboxylase... 

The ratio of peaks for peptides derived from 42 high abundance yeast proteins was examined for the wild type versus cln2 mutant strains (Oda et al., 1999). Only two of the proteins, a peroxisomal membrane protein and S-adenosylmethionine synthase 2, exhibited significant differences in expression between the strains. The biological significance of this observation is not yet known but the study does indicate that changes of >20% in expression levels can be detected using the technique (Oda et al., 1999). 

S-adenosylmethionine and N5-methyltetrahydrofolate derivatives are not capable of transferring methyl groups to mercury salts since for both these coenzymes the methyl group is transferred as CH3. 

Secondary metabolites generated via the propionate route are quite unusual in nature. Relevant exceptions are some antibiotic macrolides from Streptomycetes [42], but wholly propionate-derived macrolides are rare. This biosynthetic pathway has been well proved for erythromycin (13), where the aglycone is produced by assembling seven propionate units [43, 44], and for a few related antibiotics [45]. However, very sophisticated biosynthetic experiments [46] have established that some apparent propionate units in other macrolides (e.g., aplasmomycin [46]) from Streptomycetes could be formed either by C-methylation through S-adenosylmethionine or from glycerol. 

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