Molecular Pharmacology, Vol 10, 319-334, 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

III. Carbocyclic and Heterocyclic Amino Acids

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

1-Aminocyclopentane-1-carboxylic acid (cycloleucine) is a competitive inhibitor of the synthesis of S-adenosyl-L-methionine by purified preparations of ATP:L-methionine S-adenosyltransferase of yeast, Escherichia coli, and rat liver. This inhibition is strictly dependent upon ring size, and is abolished by the introduction of 2-alkyl or 2-nitro substituents. Of the four isomers of 3-methylcycloleucine, only 1R-amino-3R-methylcyclopentane-1-carboxylic acid has inhibitory activity comparable to cycloleucine, whereas 1S-amino-3R-methylcyclopentane-1-carboxylic acid was far less active, and the enatiomers of these compounds were inferred to be inactive. Although the negative effects of certain substitutents on inhibitory potency may be the result of lack of "bulk tolerance" in some topographical regions of the enzyme, other factors influencing physicochemical properties, bond angles, and conformations are probably of greater importance. The presence of the amino and carboxyl groups on a 5-membered ring appears to be a necessary condition for inhibition. Rigidification of the cyclic amino acid skeleton may influence the inhibitory properties profoundly. Thus 2-aminoadamantane-2-carboxylic acid lacks inhibitory activity. Of the four isomenic 2-aminonorbornane-2-carboxylic acids, only the 1R,2R,4S-isomer has significant inhibitory activity, which was slightly superior to that of cycloleucine in all three enzyme systems. The addition of an aromatic ring to the cycloleucine to create an indane skeleton depresses the inhibitory activity, whereas the addition of a second aromatic ring, as in 9-aminofluorene-9-carboxylic acid, gives an excellent inhibitor of yeast and liver enzyme with little activity for the E. coli enzyme. The effects of introduction of heteroatoms into the ring system lead to compounds with their enhanced or depressed activity. Thus 4-amino-1,2-dithiolane-4-carboxylic acid is an excellent inhibitor, superior to cycloleucine, whereas its sulfone [(RS-4-amino-1,1-dioxo-1,2-dithiolane-4-carboxylic acid] is rather less active than the disulfide. Introduction of sulfur atoms into 6-membered rings, as in 5-amino-1,3-dithiane-5-carboxylic acid and (RS)-4-amino-1,2-dithiane-4-carboxylic acid, affords compounds with little inhibitory activity. Cucurbitine (RS-3-aminopyrrolidine-3-carboxylic acid) has very little inhibitory activity, and this may be the consequence of a formal positive charge on the ring nitrogen atom at physiological pH. Two new methylmercapto derivatives of cyclic amino acids were synthesized: 1RS-amino-3RS-(methylthio)cyclopentane-1-carboxylic acid, which had some inhibitory activity associated with one of its racemic pairs, and 1RS-amino-3RS-(methylthio)cyclohexane-1-carboxylic acid, which was inactive. Some of these carbocyclic and heterocyclic amino acids possess various pharmacological activities, including the capacity to inhibit tumor growth, suppress the immune response, and block amino acid transport. The structural specificities for these activities are different. Conformational, electronic, and steric factors all require consideration in the design of inhibitors for the adenosyltransferases.

Note:
ACKNOWLEDGMENTS The authors are grateful to Mrs. Mary Karen Burch for skillful technical assistance. Drs. Harold Doshan and Timothy Karpetsky kindly carried out some of the syntheses indicated in the text. Generous gifts of a number of compounds are acknowledged in the body of this paper. We are grateful to our colleague, Dr. Cecil H. Robinson, for much valuable advice, and to Drs. J. P. Glusker and H. L. Carrell for discussion of their crystallographic analyses.

This article has been cited by other articles:

				Z. J. Lu and G. D. Markham Enzymatic Properties of S-Adenosylmethionine Synthetase from the Archaeon Methanococcus jannaschii J. Biol. Chem., May 3, 2002; 277(19): 16624 - 16631. [Abstract] [Full Text] [PDF]