A series of aromatic amino acids structurally related to L-methionine were synthesized as potential inhibitors of the enzymatic formation of S-adenosyl-L-methionine by partially purified preparations of ATP:L-methionine S-adenosyltransferase (EC 18.104.22.168) of bakers’ yeast, Escherichia coli, and rat liver. 2-Amino-5-phenylpentanoic acid was a considerably better inhibitor of the liver enzyme than 2-aminopentanoic acid (norvaline) but produced no inhibition of the yeast and E. coli enzymes. (E)-2-Amino-5-phenyl-4-pentenoic and 2-amino-5-phenyl-4-pentynoic acids were superior in their inhibitory activity to the corresponding chain-saturated analogues. The phenyl group thus imparts a favorable influence on the inhibitory power. S-Phenyl-DL-homocysteine is an even more potent inhibitor of the liver enzyme, but is also devoid of activity in the microbial enzyme systenms. O-Phenyl-DL-homoserine displays similar properties, but was not quite as effective as the sulfur analogue. In order to evaluate the effect of electron-donating and electron-withdrawing substituents on the phenyl ring, the following compounds were synthesized: O-(p-fluorophenyl)-DL-homoserine, O-(p-chlorophenyl)-DL-homoserine, O-(p-bromophenyl)-DL-homoserine, O-(p-nitrophenyl)-DL-homosenine, O-(p-methoxyphenyl)-DL-homoserine, O-(p-methylphenyl)-DL-homoserine, O-(m-chorophenyl)-DL-homoserine, O-(m-bromophenyl)-DL-homoserine, O-(m-nitrophenyl)-DL-homoserine, and O-(m-methoxyphenyl)-DL-homoserine. When the inhibitory potencies of these compounds (expressed as pI50 values) were analyzed in terms of the Hammett σ values of the substituents, the inhibitory potency was correlated with the positive magnitudes of the σ values. If the anomalous nitro compounds are excluded, the Hammett sigma-rho equation PI50 = 1.45σ + 1.82 is obtained by least-squares linear regression analysis. This finding suggests that the electron-withdrawing substituents are most favorable for inhibition, and that the creation in the analogue of a partial positive charge at the heteroatom bearing the phenyl group may resemble most closely the transition state of the enzymatic reaction, in which the thioether group of L-methionine is converted to the positively charged sulfonium group of S-adenosyl-L-methionine. O-Methyl-DL-homoserine is a strong inhibitor of the adenosyltransferases of yeast, E. coli, and rat liver, and especially powerful for the E. coli enzyme. Since it has been shown that this compound inhibits the growth of certain microorganisms and viruses, as well as displaying certain specific toxicities in rodents the possibility should be considered that these effects are due to inhibition of the adenosyltransferase reaction.
ACKNOWLEDGMENTS The authors are grateful to Mrs. Mary Karen Burch, Mrs. JoAnn Kaufmann, and Mrs. Patricia M. Margulies for skillful assistance in various aspects of these studies. We wish to thank Dr. Cathrine Fenselau for consultation on mass spectrometric analyses, and Dr. Cecil H. Robinson for much valuable advice. Miss Rachel Talalay assisted with some of the regression analyses.
- Copyright ©, 1974, by Academic Press, Inc.