title: Aminoacyl analogs of chloramphenicol: examination of the kinetics of inhibition of peptide bond formation.
abstract: Two aminoacyl analogs and one peptidyl analog of chloramphenicol (1, Cl2CHCO-CA) were prepared. These are 2 (L-Phe-CA), 3 (Gly-CA), and 4 (L-Phe-Gly-CA). The kinetics of inhibition of peptide bond formation by these analogs were examined in a cell-free system which was derived from E. coli and used previously for the study of 1 (Drainas; et al. Eur. J. Biochem. 1987, 164, 53-58). In the absence of inhibitor, the reaction follows first-order kinetics for the entire course of the reaction. In the presence of the analog the reaction gives biphasic log-time plots. The kinetic information pertaining to the initial slope of the plot is analyzed (initial-slope analysis). This information differentiates the analogs from the parent compound 1. The parent compound 1 gives complex inhibition kinetics; increasing the concentration of 1 changes the inhibition from competitive to mixed noncompetitive (Drainas; et al. Eur. J. Biochem. 1987, 164, 53-58). In contrast, the analogs give competitive kinetics even at high concentrations of the inhibitor. The following Ki values have been determined: 18.0 microM for 2, 5.5 microM for 3, 1.5 microM for 4. If we were to assume that compounds 2, 3 and 4 behave as classical competitive inhibitors, we could say that 4 is 12 times more potent than 3 and 4 times more potent than 2. On this assumption we could also compare 1 with 4 and see that 4 is 2 times weaker than 1. It is suggested that as compared with 1, the two aminoacyl analogs and the dipeptidyl analog have increased structural similarity to the 3'-terminus of aminoacyl-tRNA or of peptidyl-tRNA and that this similarity results in a more pronounced competitive inhibition.
authors.affiliation: Laboratory of Biochemistry, School of Medicine, University of Patras, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Drainas
authors.forename: P
authors.initials: P
authors.lastname: Mamos
authors.forename: C
authors.initials: C
authors.lastname: Coutsogeorgopoulos
mesh_terms: D001667:Binding, Competitive; D002701:Chloramphenicol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D007700:Kinetics; D015394:Molecular Structure; D010455:Peptides / Q000378:metabolism*; D011072:Poly U / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D011500:Protein Synthesis Inhibitors; D012346:RNA, Transfer, Amino Acyl; C006383:tRNA, N-acetylphenylalanine-; D011072:Poly U; D002701:Chloramphenicol