Formation, functions and regulatory importance of S-adenosyl-l-methionine

Summary The present status of knowledge of the synthesis and the metabolic and regulatory functions of S -adenosyl- l -methionine (AMe) is reviewed. The mechanism of the enzymatic synthesis of AMe from ATP from ATP and l -methionine by the ATP: l -methionine adenosyltransferase has been examined extensively and appears to be well characterized. However, recent kinetic investigations have uncovered complex deviations from classical Michaelis-Menten kinetics and suggest that the enzyme may be endowed with regulatory properties. The substrate specificity of ATP: l -methionine adenosyltransferase was found to be quite rigid. Only a few closely related analogues of methionine can be activated to their S -adenosylmethionine-derivatives by enzyme preparations obtained from yeast, E. coli and rat liver. A myriad of methionine analogues were also tested as inhibitors of the reaction in order to determine the conformation of l -methionine at the enzyme active site. In addition to dl -2-amino-4- trans -hexenoic acid, an acetylenic amino acid ( l -2-amino-4-hexynoic acid) and a cyclic amino acid (l-aminocyclopentanecarboxylic acid), all of which lack a sulfur atom, have been found to be the most potent inhibitors. The distribution of adenosyltransferase enzyme, in normal and malignant tissues, appears to be ubiquitous although the enzyme is most active in liver and moderately active in kidney and pancreas. The effects of steroid hormones, age and diet on the enzyme activities are reviewed. In addition to the widely recognized functions of AMe as a methyl group donor for transmethylations and as a propylamine donor for polyamine synthesis, a number of regulatory roles including feedback inhibitions and allosteric modifiers have been recently recognized. S -Adenosyl- l -methionine synthesis appears to be self-regulating in that AMe stimulates the hydrolysis of tripolyphosphate, an obligatory enzyme-bound intermediate. The complex B 12 -dependent methylation of l -homocysteine to l -methionine, utilizing N 5 -methyltetrahydrofolate, also requires AMe in what appears to be a priming methylation of the initial molecules of B 12 . Methionine biosynthesis in microbial systems is under feedback control. The enzymes involved in the formation of O -succinyl- l -homoserine and O -acetyl- l -homoserine (intermediates in the pathway of methionine bio-synthesis), in E. coli and yeast, respectively, are inhibited by S -adenosyl- l -methionine. However, in Neurospora the homoserine transacetylase reaction is unaffected by AMe but the following enzyme in the pathway, cystathionine synthetase, catalyzing the condensation of cysteine with O -acetyl- l -homoserine is powerfully inhibited. The allosteric effect of AMe in the lysine 2,3-aminomutase reaction and the requirement of AMe for bacteriophage restriction enzymes are described. The metabolism of S -adenosyl- l -methionine is examined and the implications of the major metabolic degradative pathways are discussed in detail both in mammalian and microbial systems. Data on S -adenosyl- l -methionine levels of normal mammalian tissues are presented together with information on the perturbation of these levels under various physiological and pharmacological conditions. Tissue levels of AMe are affected by administration of: (a) l -methionine, (b) drugs which are known methyl group acceptors, (c) monoamine oxidase inhibitors, and (d) analogues of methionine which are inhibitors of ATP: l -methionine adenosyltransferase reaction, specifically, l -2-amino-4-hexynoic and 1-aminocyclopentanecarboxylic acid. The latter two compounds when administered to male rats bearing the Walker-256 sarcoma and male mice bearing the Lewis lung tumor were found to increase the liver levels of AMe (50–100%) while decreasing these levels in the tumor (30–50%). A possible explanation for these opposing effects in the liver and tumors is obtained from in vitro data which show a stimulatory effect on the adenosyltransferases at low concentrations of these inhibitors. Data concerning the turnover rates of S -adenosyl- l -methionine in various mammalian tissues are also presented and discussed.