Structural and conformational analogues of L methionine as inhibitors of the enzymatic synthesis of S adenosyl L methionine. II. Aromatic amino acids

A. W. Coulter, J. B. Lombardini, P. Talalay

Research output: Contribution to journalArticlepeer-review

Abstract

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 2.5.1.6) 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 systems. 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 homoserine, O (p methoxyphenyl) DL homoserine, O (p methylphenyl) DL homoserine, O (m chlorophenyl) 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 sigma values of the substituents, the inhibitory potency was correlated with the positive magnitudes of the sigma values. If the anomalous nitro compounds are excluded, the Hammett sigma rho equation pI50 = 1.45 sigma + 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 raction, 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.

Original languageEnglish (US)
Pages (from-to)305-314
Number of pages10
JournalMolecular Pharmacology
Volume10
Issue number2
StatePublished - Jan 1 1974

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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