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

Aliphatic amino acid analogues of L methionine that inhibit the enzymatic synthesis of S adenosyl L methionine were designed on the basis of structural, conformational, and electronic considerations. The inhibitory activity of these compounds was evaluated with partially purified preparations of ATP:L methionine S adenosyltransferase (EC 2.5.1.6) obtained from bakers' yeast, E. 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 were analyzed in an effort to deduce the most favorable 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).