5-Adenosylmethionine methylation

Arsenic detoxification and evolution of trimethylarsine gas by a microbial arsenite S-adenosylmethionine methyl-transferase. Proc. Natl Acad. Sci. USA 103 2075-80. 

Some of the most common biological Sn2 reac tions involve attack at methyl groups especially a methyl group of S-adenosylmethionine Examples of these will be given in Chapter 16... 

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. 

Adenosylmethionine, the principal source of methyl groups in the body, also contributes its carbon skeleton for the biosynthesis of the 3-diaminopropane portions of the polyamines spermine and spermidine (Figure 31-4). 

Adenosylmethionine, the methyl group donor for many biosynthetic processes, also participates direcdy in spermine and spermidine biosynthesis. 

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. 

The possibility that synthesis of the HGA in tobacco membranes might be limited by the lack of methyl donor was ruled out since the addition of exogenous S-adenosylmethionine, a methyl donor known to function in the methylesterification of pectin (41,70), did not... 

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. 

As would be expected, the chemistry is complex. Unpleasant, off flavor odors usually derive from sulfur compounds, such as MT, DMS, DMDS, and DMTS, formed either enzymatically or non-enzymatically from sulfur-containing amino acids.35 Enzymatic routes to MT are essentially those previously considered (Section 11.1.2.4.5). Some DMS may derive by methylation of MT (Equation 8) with the donor, 5-adenosylmethionine, AdoMet ... 

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