The International Journal of Biochemistry & Cell Biology
Molecules in focusMethylthioadenosine
Introduction
The natural existence of the sulfur-containing nucleoside methylthioadenosine [5′-deoxy-5′-methylthioadenosine; adenine-9-β-D (5′-deoxy-5′-methylthio) ribofuranoside], commonly abbreviated as MTA and occasionally as MeSAdo, was realized almost a century ago (Williams-Ashman, Seidenfeld, & Galletti, 1982). Its molecular structure was reported in 1924, and the biological importance of MTA became apparent in 1952, 1 year before the discovery of its metabolic precursor S-adenosylmethionine (AdoMet, also abbreviated as SAM and SAMe), in studies on the metabolic interrelationship of methionine and 5-thiomethylribose (Williams-Ashman et al., 1982). MTA is present in small amounts in all cell types, including prokaryotes, yeast, plants and higher eukaryotes. In mammalian tissues, MTA is mainly produced during the biosynthesis of polyamines (Williams-Ashman et al., 1982, Pegg, 1988). For many years, this nucleoside has received by far much less attention than its precursor AdoMet. However, information accumulated over the past two decades evidences a wide variety of potent and specific effects of MTA upon its interaction with mammalian cells and tissues. The present review summarizes what is known about MTA synthesis and degradation, its biological functions and its potential therapeutic applications.
Section snippets
Structure
MTA is a hydrophobic sulfur-containing adenine nucleoside in which the hydroxyl group in the 5′ position of the ribose is substituted by a methylthio moiety (Fig. 1). This methylthio moiety is derived from the amino acid methionine, while the rest of the molecule comes from ATP.
Synthesis and degradation
MTA is produced from AdoMet by different processes in a variety of organisms (Williams-Ashman et al., 1982). MTA can be produced by the cleavage of one of the AdoMet SC bonds with the concomitant production of homoserine lactone. This process is catalyzed by AdoMet cyclotransferase, an enzyme present in yeast, certain bacteria and mammalian liver (Williams-Ashman et al., 1982). However, little is known about the quantitative contribution of this pathway to MTA synthesis. The major source of
Biological functions
As can be inferred from above, MTA is located at a crossroad in cellular metabolism. MTA is a metabolic product of AdoMet in polyamine biosynthesis, and at the same time the starting point of two major salvage pathways. Besides its role as a metabolic intermediate, MTA may play relevant regulatory functions in the cell. Some of these functions, such as its inhibitory effects on spermidine and spermine synthase and on ODC, have been already outlined. In addition, a wide variety of biological
Possible medical applications
MTA is a natural compound with potent pharmacological effects. The administration in vivo of high doses of MTA in experimental models of acute and chronic liver damage and liver carcinogenesis has proved to be beneficial, and without major toxicological manifestations. Besides, our unpublished observations demonstrate a powerful anti-inflammatory profile for this molecule. Although systematic studies on the pharmacokinetics and toxicity of MTA are lacking, and its mechanism or mechanisms of
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