Molecules in focus
Methylthioadenosine

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Abstract

5′-Methylthioadenosine (MTA) is a naturally occurring sulfur-containing nucleoside present in all mammalian tissues. MTA is produced from S-adenosylmethionine mainly through the polyamine biosynthetic pathway, where it behaves as a powerful inhibitory product. This compound is metabolized solely by MTA-phosphorylase, to yield 5-methylthioribose-1-phosphate and adenine, a crucial step in the methionine and purine salvage pathways, respectively. Abundant evidence has accumulated over time suggesting that MTA can affect cellular processes in many ways. MTA has been shown to influence numerous critical responses of the cell including regulation of gene expression, proliferation, differentiation and apoptosis. Although most of these responses have been observed at the pharmacological level, their specificity makes it tempting to speculate that endogenous MTA could play a regulatory role in the cell. Finally, observations carried out in models of liver damage and cancer demonstrate a therapeutic potential for MTA that deserves further consideration.

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 SC 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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