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Inhibition of Protein Synthesis in Vitro and in Vivo by Nucleocidin, an Antitrypanosomal Antibiotic

From the ¹ From the Biochemistry Research Department, Biochemical Research Section, Lederle Laboratories Division, American Cyanamid Company, Pearl River, New York 10965

The inhibition by nucleocidin of amino acid incorporation into protein exhibited the following characteristics.

1. Inhibition occurs at a stage subsequent to the formation of aminoacyl-soluble ribonucleic acid (S-RNA). The transfer of labeled amino acid from S-RNA to protein is inhibited by nucleocidin, but only in the presence of pH 5 fraction.

2. Nucleocidin inhibits labeling of peptides associated with polyribosomes but has no effect on the release of prelabeled peptides from ribosomes. Prior incubation with nucleocidin does not inhibit the release of labeled peptides from ribosomes when puromycin is added to the reaction mixture.

3. There is an appreciable lag period before inhibition is observed, indicating a requirement for a process which is slow relative to peptide bond formation. Prior incubation of the system with nucleocidin eliminates the lag period and strikingly enhances inhibition of incorporation; all components of the incorporating system must be present during the preliminary incubation for these effects to occur.

4. Ribosomes reisolated after incubation with nucleocidin are less active in the transfer reaction; this inhibition is reversible and the reversal is stimulated by addition of pH 5 fraction.

5. Nucleocidin does not inhibit the binding of ³²P-S-RNA to ribosomes. A previous observation which indicated that nucleocidin inhibited the binding of ³H-leucyl-S-RNA was repeated, but it appears that calculation of the radioactivity removed by treatment with hot trichloroacetic acid probably does not give a valid estimate of the effects of inhibitors on S-RNA binding to ribosomes.

6. Incorporation of amino acid stimulated by a synthetic polynucleotide is inhibited by nucleocidin to the same extent as unstimulated incorporation.

7. Nucleocidin is the most potent inhibitor of protein synthesis in vivo of any antibiotic reported thus far, although it exhibits no greater potency in vitro.

8. Comparisons with reports of the effects of other antibiotics on amino acid incorporation into protein in vitro and in vivo indicate that the mechanism of action of nucleocidin differs from those reported for any other antibiotic.

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