5-Adenosylmethionine, from

The formation of this complex cofactor occurs in one of only two known reactions in which triphosphate is cleaved from ATP (Fig. 3) the other reaction is the formation of 5-adenosylmethionine from ATP and methionine (see Fig. 18-18). 

Adenosine triphosphate, coupled reactions and. 1128-1129 function of, 157, 1127-1128 reaction with glucose, 1129 structure of, 157, 1044 S-Adenosylmethionine, from methionine, 669 function of, 382-383 stereochemistry of, 315 structure of, 1045 Adipic acid, structure of, 753 ADP, sec Adenosine diphosphate Adrenaline, biosynthesis of, 382-383 molecular model of, 323 slructure of, 24... 

After dealing only with simple halides such as iodomethane used for laboratory alkylations, it s something of a shock to encounter a molecule as complex as S-adenosylmethionine. From a chemical standpoint, however, CH3I and S-adenosylmethionine do exactly the same thing Both transfer a methyl group by an S>j2 reaction. The same principles of reactivity apply to both. 

Scheme V, Synthesis of chiral (S)-adenosylmethionine from chiral acetate.

How many high-energy bonds are expended during the synthesis of S-adenosylmethionine from ATP and methionine ... 

The methyl transfer from methionine has been reported to depend on the formation of S-adenosylmethionine from methionine and ATP. 

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). 

Cacciapuoti G, M Porcelli, M de Rosa, A Gambacorta, C Bertoldo, V Zappia (1991) 5 -adenosylmethionine decarboxylase from the thermophilic archaebacterium Sulfolobus solfataricus. Putification, molecular properties and studies on the covalently bound pyruvate. Eur J Biochem 199 395-400. 

Lu ZJ, GD Markham (2004) Catalytic properties of the archaeal 5-adenosylmethionine decarboxylase from Methanococcus jannaschii. J Biol Chem 279 265-273. 

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). 

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 ... 

As for tin, two potential routes to methyllead compounds might appear to exist (1) Me carbanion attack on lead(II) (e.g. by Me- from MeCoBn) followed by dismutation and (2) oxidative addition by a Me+ carbonium ion from e.g. S adenosylmethionine or Mel etc. 

In cells that synthesize epinephrine, the final step in the pathway is catalyzed by the enzyme phenylethanolamine /V-methyltransferase. This enzyme is found in a small group of neurons in the brainstem that use epinephrine as their neurotransmitter and in the adrenal medullary cells, for which epinephrine is the primary hormone secreted. Phenylethanolamine N-methyltransferase (PNMT) transfers a methyl group from S-adenosylmethionine to the nitrogen of norepinephrine, forming a secondary amine [5]. The coding sequence of bovine PNMT is contained in a... 

Transfer of a methyl group from S-adenosylmethionine yields S-adenosylhomocysteine, which potently inhibits several methyltransferases this may partially explain the pathology of homocystinuria. Tissue levels of S-adenosylhomocysteine ordinarily are very low, since this metabolite is rapidly cleaved by a specific hydrolase to homocysteine and adenosine (Fig. 40-4 reaction 3). 

The best characterized B 12-dependent methyltransferases is methionine synthase (Figure 15.11) from E. coli, which catalyses the transfer of a methyl group from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate. During the catalytic cycle, B12 cycles between CH3-Co(in) and Co(I). However, from time to time, Co(I) undergoes oxidative inactivation to Co(II), which requires reductive activation. During this process, the methyl donor is S-adenosylmethionine (AdoMet) and the electron donor is flavodoxin (Fid) in E. coli, or methionine synthase reductase (MSR) in humans. Methionine synthase... 

A minor pathway to synthesize PC, which is mainly active in liver cells, utilizes the enzyme phosphatidylethanolamine-A-methyltransferase (PEMT), which converts phosphatidylethanolamine (PE) to PC by the subsequent transfer of three methyl groups from S-adenosylmethionine (Vance et al, 1997). The PEMT pathway, which links PE synthesis to PC, was found to be critical for PC homeostasis in the Uver dining choline deficiency (Walkey et al, 1997). 

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. ... 

Phosphatidylcholine can also be produced from phosphatidylethanolamine by methylation which involves the methylating agent S-adenosylmethionine as follows ... 

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