Molecular Pharmacology, Vol 10, 293-304, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Structural and Conformational Analogues of L-Methionine as Inhibitors of the Enzymatic Synthesis of S-Adenosyl-L-methionine

I. Saturated and Unsaturated Aliphatic Amino Acids

¹ Department of Pharmacology and Experimental Therapeutics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Aliphatic amino acid analogues of L-methionine that inhibit the enzymatic synthesis of S-adenosyl-L-methionine have been designed onthe basis of structural, conformational, and electronic considerations. The inhibitory activity of these compounds has been evaluated with partially purified preparations of ATP:L-methionine S-adenosyltransferase (EC 2.5.1.6) obtained from bakers’ yeast, Escherichia coli, and rat liver. The effects of variation in length and branching of carbon chain, steric configuration, degree or position of unsaturation, and the introduction of chloro groups have been analyzed in an effort to deduce the most favourable features for inhibition. Within this class of compounds, 2-amino-4-hexynoic acid, (E)-2-amino-trans-4-hexenoic acid, and (Z)-2-amino-5-chloro-trans-4-hexenoic acid are among the most powerful inhibitors synthesized. In contrast, (Z)-2-amino-cis-4-hexenoic acid and (E)-2-amino-5-chloro-cis-4-hexenoic acid are weak inhibitors or are inactive. The activity of the more powerful inhibitors appears to reside exclusively in the L isomers. (Z)-L-2-Amino-5-chloro-trans-4-hexenoic acid displays considerably greater specificity for the inhibition of rat liver enzyme (I₅₀ = 0.55 mM) than for the yeast (I₅₀ = 3.0 mM) or E. coli (I₅₀ = 4.2 mM) adenosyltransferase. Examination of molecular models reveals a close similarity in the size, shape, and molecular contour between an extended conformation of L-methionine and L-2-amino-4-hexynoic acid and (Z)-L-2-amino-5-chloro-trans-4-hexenoic acid. Another compound with significant inhibitory activity is (2S, 4S)-2-amino-4,5-methylene-5-hexenoic acid (hypoglycin A).

Note:
ACKNOWLEDGMENTS The authors are grateful to Mrs. Mary Karen Burch, Mrs. JoAnn Kaufmann, Mrs. Patricia M. Margulies, and Mrs. Jean Salt for skillful assistance in various aspects of these studies. Valuable gifts of various compounds are acknowledged in the text. We are also grateful to our colleague, Dr. C. H. Robinson, for much valuable advice.

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