Dual effect of chloramphenicol peptides on ribosome inhibition
| Autor: | Ioannis A. Vlachogiannis, Stefan Arenz, Anthony Bougas, Dimitrios Gatos, George P. Dinos |
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| Rok vydání: | 2017 |
| Předmět: |
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Molecular 0301 basic medicine Peptidyl transferase Green Fluorescent Proteins Clinical Biochemistry Peptide Internal Ribosome Entry Sites Biology Biochemistry Ribosome 03 medical and health sciences 0302 clinical medicine 23S ribosomal RNA medicine Amino Acid Sequence Binding site 50S Protein Synthesis Inhibitors chemistry.chemical_classification Fluorenes Binding Sites Escherichia coli K12 Chloramphenicol Organic Chemistry Ribosomal RNA 030104 developmental biology chemistry Protein Biosynthesis Peptidyl Transferases biology.protein Puromycin Peptides Poly A Ribosomes 030217 neurology & neurosurgery Protein Binding medicine.drug |
| Zdroj: | Amino Acids. 49:995-1004 |
| ISSN: | 1438-2199 0939-4451 |
| DOI: | 10.1007/s00726-017-2406-5 |
| Popis: | Chloramphenicol peptides were recently established as useful tools for probing nascent polypeptide chain interaction with the ribosome, either biochemically, or structurally. Here, we present a new 10mer chloramphenicol peptide, which exerts a dual inhibition effect on the ribosome function affecting two distinct areas of the ribosome, namely the peptidyl transferase center and the polypeptide exit tunnel. According to our data, the chloramphenicol peptide bound on the chloramphenicol binding site inhibits the formation of both acetyl-phenylalanine-puromycin and acetyl-lysine-puromycin, showing, however, a decreased peptidyl transferase inhibition compared to chloramphenicol-mediated inhibition per se. Additionally, we found that the same compound is a strong inhibitor of green fluorescent protein synthesis in a coupled in vitro transcription-translation assay as well as a potent inhibitor of lysine polymerization in a poly(A)-programmed ribosome, showing that an additional inhibitory effect may exist. Since chemical protection data supported the interaction of the antibiotic with bases A2058 and A2059 near the entrance of the tunnel, we concluded that the extra inhibition effect on the synthesis of longer peptides is coming from interactions of the peptide moiety of the drug with residues comprising the ribosomal tunnel, and by filling up the tunnel and blocking nascent chain progression through the restricted tunnel. Therefore, the dual interaction of the chloramphenicol peptide with the ribosome increases its inhibitory effect and opens a new window for improving the antimicrobial potency of classical antibiotics or designing new ones. |
| Databáze: | OpenAIRE |
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