5 -Methylthioadenosine synthesis

The synthesis of 964 was achieved by coupling 6-chloropurine and 4-methylthiobutan-l-ol (962) under the influence of DEAD/PhaP to give 963, followed by ammonolysis to 964 [93JCS(P1)1109], It was a potent inhibitor of the enzyme methylthioadenosine nucleosidase. 

Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP in many tissues, by a reaction similar to that of hypoxanthine-guanine phosphoribosyltransferase, but is quite distinct from the latter. It plays a minor role in purine salvage since adenine is not a significant product of purine nucleotide catabolism (see below). The function of this enzyme seems to be to scavenge small amounts of adenine that are produced during intestinal digestion of nucleic acids or in the metabolism of 5 -deoxy-5 -methylthioadenosine, a product of polyamine synthesis. 

AdoMet is an important metabolic intermediate in all organisms, from bacteria to higher animals and plants. It supplies the methyl group to nucleic acids, phenolic substances and alkaloids, or the propylamine moiety to polyamines after decarboxylation. The methionine cycle operates in animals and microorganisms in relation to polyamine synthesis. Thus, enzymes which catalyse all of these reactions are present in all organsims. However, two enzymes in the ACC pathway, ACC synthase (AdoMet methylthioadenosine-lyase) and ACC oxidase, are unique to higher plants. ACC is also malonylated to form N-malonyl ACC, which does not serve as a precursor of ethylene [48,49]. 

S ATP + 5-methylthioribose (<1> enzyme may be involved in an alternative pathway of methionine synthesis in plant tissues [1] <2> may be a primary enzyme involved in the recycling of the methylthio group of 5-methylthioribose back into methionine [2,3] <3> key step in recycling of methionine from 5 -methylthioadenosine a co-product of polyamine biosynthesis, expression of methylthioribose kinase may be under control of the methionine regulon [4]) (Reversibility [1-4, 6]) [1-4, 6, 7]... 

The reaction -will begin with the formation of a Schiff base between pyridoxal-5 -phos-phate and the amino group of 5-adenosylmethionine (external aldimine, as opposed to the internal aldimine in which PLP is connected to a lysine on the enzyme). In usual fashion for PLP enzymes, the a-hydrogen -will be extracted from S-adenosylmethionine (step 2, below). Then the next series of 7i-electron transfers (step 3) will eliminate S-methylthioadenosine and form the three-membered ring. Finally, f-aminocyclopropane-1-carboxylate (ACC) will be released, and the original internal aldimine between PLP and lysine veill be restored, so that the enzyme and cofactor are ready for another round of synthesis. The second product is S-methylthioadenosine. 

The complex reactions of a second recycling pathway lead to the synthesis of Met 8 from methylthioadenosine (MTA 9). The methylthio group of Met derives from MTA and is not built upon methylation of homocysteine 8. This pathway is not known in mammals [32],... 

An improved route has been described for the synthesis of 5 -5-aryl (or alkyl)-5 -thionucleosides,7 and it has been shown that the S-aryl compounds can be oxidized directly to 5 -fluoro-5 -thionucleoside derivatives using XeP2, in addition to the two-stage process involving oxidation to the sulfoxide and then treatment with DAST to induce a Pummerer-type process (see Vol. 22, p.212). Further oxidation of the a-fluorosulfides gives sulfones such as (9l).li3 Another reference to the use of such intermediates was discussed earlier, and there has been a further report on the preparation of 5 -(fluoromethylthio)adenosine and 5 -fluoro-5 -methylthioadenosine from the methylsulfinyl derivative and DAST (see Vol. 23, p.216)H - 5 -(Di- and trifluoromethylthio)adenosine have been prepared by alkylation with the appropriate chlorofluoromethane,H as have fluorinated 5-ethyl compounds of type (92),115.ll6 and the 5-(3-fluoropropyl)analogue.H9 The cyclic... 

Inhibition of RNA synthesis in salivary glands of Drosophila melanogaster by 5 -methylthioadenosine, Biochem. Biophys. 

Fig, 7. Pathways for the metabolism of methionine to 5 -methylthioadenosine (MTA) and recycling of MTA to methionine. Methionine can serve as a carbon source for the synthesis of polyamines and, in some tissues, ethylene. 5 -Methylthioadenosine is a product of both processes. Only the methylthio group of methionine is recycled, the C4 moiety for the resynthesis of methionine being derived from the ribosyl moiety of ATP. The enzymes involved are (1) SAM synthetase, (2) SAM decarboxylase, (3) various C3 transfer enzymes of polyamine biosynthesis, (4) MTA nucleosidase, (5) methylthioribose kinase, (6) three( ) uncharacterized enzymes, (7) aminotransferase, and (8) aminocyciopropane carboxylate synthase. 

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