5 -Methylthioadenosine metabolism

When 2, 3 -dl-0-acetyl-5 -deoxy-5 -aryl(alkyl)sulphinyladenoslnes were treated with DAST and catal3rtic SbCla, followed by deacylatlon, novel fluorothionucleosides of type (33) were produced. These compounds, rather unstable for the case R=Me, were designed as potential inhibitors of S-adenosylhomocysteine and methylthioadenosine metabolism.78 The adenosine derivative (34) has been prepared in connection with studies of enzyme inhibition. 79... 

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. 

Adams and Yang (10) have suggested that the S atom of methionine is recycled in the ethylene reaction pathway, as shown in Fig. 2. In this scheme, 5 -methylthioadenosine, the residual molecule which derives from the reaction converting SAM to ACC, is further metabolized to 5 -methylthioribose, which then transfers the S-methyl group to homoserine to form methionine. This scheme is hypothetical, and the enzymes necessary for all these reactions have not as yet been demonstrated. 

Porcelli, M., Cacciapuoti, G., Cimino, G., Gavagnin, M., Sodano, G., and Zappia, V., Biosynthesis and metabolism of 9-[5 deoxy-5 -(methylthio)-P-D-xylofuranosyl]adenine, a novel natural analogue of methylthioadenosine, Biochem. J., 263, 635, 1989. 

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]. 

Metabolism of AdoMet in plants yields two main nucleoside products, AdoHcy and 5 -methylthioadenosine. The metabolism of these compounds is outlined below. 

The chemical identity of the methylthio group formed in Eq. (16) has not been established. The enzyme catalyzing Eq. (15) was observed only in extracts of cells that grew well without addition of methylthio compounds. This finding raises the intriguing possibility that 5 -methylthioadenosine may be an essential product of AdoMet metabolism, and that there may be a general requirement for methylthio or related groups for cell division. 

Methylthioadenosine (MTA) represents one of the main products of S-adenosylmethionine (Ado-Met) metabolism and is distributed ubiquitously in micromolar amounts in several prokaryotes and eukaryotes . Although the chemical structure of this thioether was elucidated in 1924, its biological role as product of methionine metabolism was demonstrated by Schlenk in 1952, even before the discovery of its precursor Ado-Met. ... 

V. Zappia, Studies on the metabolism of 5 -isobutylthioade-nosine (SIBA). Phosphorolytic cleavage by methylthioadenosine phosphorylase, FEBS Letters in press (1979). 

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. 

---