Molecular Pharmacology, Vol 6, 481-499, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Analogues of Methionine as Substrates and Inhibitors of the Methionine Adenosyltransferase Reaction

Deductions Concerning the Conformation of Methionine

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

Steric, electronic, and conformational requirements are described for analogues of L-methionine essential to their function as substrates or inhibitors of the methionine adenosyltransferase reaction (ATP: L-methionine S-adenosyltransferase, EC 2.4.2.13). With the aid of partially purified transferase preparations from Escherichia coli, bakers' yeast, and rat liver, a systematic study of substrate analogues has been undertaken. Inhibitors of the enzyme fall into three categories: (a) straight carbon chain amino acids, such as L-2-amino-4-hexenoic acid (trans but not the cis isomer) and L-2-amino-4-hexynoic acid, which are the most potent inhibitors; (b) cyclic amino acids, among which 1-aminocyclopentanecarboxylicacid and one of the four isomers of 1-amino-3-methylcyclopentanecarboxylic acid (either the 1R, 3R or the 1S, 3R isomer) are the most powerful; and (c) O-acetyl-L-serine-O-carbamyl-L-serine, and S-carbamyl-L-cysteine. Since inhibitors belonging to groups (a) and (b) possess considerable conformational rigidity by virtue of the presence of unsaturations or cyclic structures, it has been possible to draw conclusions with respect to the conformation of L-methionine at the active site of the adenosyltransferase reaction. A number of the inhibitors of the methionine adenosyltransferase reaction, such as 1-aminocyclopentanecarboxylic acid and S-carbamyl-L-cysteine, are known to be inhibitors of the growth of certain microorganisms and tumors. The possibility is suggested that these inhibitory activities may be mediated at least in part through the inhibition of the synthesis of S-adenosyl-L-methionine.

Note:
ACKNOWLEDGMENTS The authors are deeply grateful to Drs. E. Bueding and C. H. Robinson for advice, and to Mrs. Mary Karen Burch for technical assistance.

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