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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
There is a wide diversity of antibiotics designed to target bacterial protein synthesis. Tetracycline antibiotics are a broad spectrum class of antibiotics that also bind to the 30S subunit, but have a different mode of action. They prevent aminoacyl tRNA from binding and stop growth of the protein. Other antibiotics target the 50S subunit of ribosomes, such as chloramphenicol, and work by inhibiting the movement of ribosomes along the mRNA strand. Chloramphenicol is the drug of choice for treating typhoid in some parts of the world, where more expensive drugs cannot be afforded.
Biochemical Aspects of Fatty Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Amino-acid activation requires ATP to form aminoacyl-AMP. The last substance will then react with the specific tRNA to form aminoacyl-tRNA. A lack in ATP or a decrease in the activity of the enzymes involved may decrease the formation of aminoacyl-tRNAs, with the consequent decline in protein synthesis.
The Cell and Cell Division
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
When the mature mRNA reaches the cytoplasm after passing through the nuclear pores, it becomes attached to ribosomes, which catalyze the production of a peptide chain. Each amino acid is brought to the ribosome by its own specific small molecule of RNA, the tRNA (Fig. 30), which has an “anticodon” at its base corresponding to the codon for that particular amino acid. Specific enzymes couple specific amino acids to their particular tRNA molecule after the amino acid is activated by the attachment of AMP, after which it is known as adenylated amino acid. The tRNA connected to its amino acid is referred to as an aminoacyl tRNA because of the bond between the amino acid and the tRNA. These mechanisms ensure that the right amino acid is brought by the correct tRNA to its specified position within the peptide chain. The genetic code is degenerate because most amino acids are coded for by more than one triplet, so that there is more than one tRNA for each amino acid, and a single tRNA can bind with more than one codon. Many amino acids require that the codon is accurate only in its first two positions (Table 2) and will tolerate “wobble” in the third position. Each incoming amino acid is attached to the carboxy end of the growing peptide chain.
An efficient system for bioconjugation based on a widely applicable engineered O-glycosylation tag
Published in mAbs, 2021
Thomas V. Murray, Kasia Kozakowska-McDonnell, Adam Tibbles, Annabel Taylor, Daniel Higazi, Emmanuel Rossy, Alessandra Rossi, Sivaneswary Genapathy, Giulia Tamburrino, Nicola Rath, Natalie Tigue, Vivian Lindo, Tristan Vaughan, Monika A. Papworth
Numerous strategies have been developed that co-opt the endogenous biosynthetic machinery to generate biomolecules containing bio-orthogonal functional groups that can be used for site-specific bioconjugation.5 Such approaches exploit the endogenous pathways at three different levels: 1) transcriptionally by the expansion of the genetic code and codon reassignment;6 2) translationally by the evolution of bio-orthogonal aminoacyl-tRNA synthetase/tRNA pairs,7 which facilitate the incorporation of unnatural amino acids; and 3) post-translationally, by modifying glycosylation,8 phosphorylation,9 and lipidation10 patterns, among others. Metabolic glyco-engineering (MGE) approaches (reviewed by Agatemor et al.8) that manipulate cellular metabolism to generate functionalized glycoproteins have become an attractive method for the generation of bioconjugates because they bypass technical challenges of other techniques, such as the requirement for the transfection of multicomponent codon reassignment machinery for unnatural amino acid incorporation or complex post-production steps required by in vitro enzymatic post-translational approaches.
Utility of boron in dermatology
Published in Journal of Dermatological Treatment, 2020
David G. Jackson, Leah A. Cardwell, Elias Oussedik, Steven R. Feldman
Aminoacyl-tRNA synthetases facilitate protein synthesis by catalyzing the attachment of the proper amino acid to the tRNA. Certain aminoacyl-tRNA synthetases, such as leucyl-tRNA synthetase, have editing sites which provide proofreading capability and assurance of correct amino acid attachment. Tavaborole, a boron-based therapy for onychomycosis inhibits the fungal leucyl tRNA-synthetase thereby preventing synthesis of leucyl-tRNA and proteins (20). The boron atom in the oxaborole ring of tavaborole is vital to this mechanism of leucyl-tRNA synthetase inhibition. Tavaborole forms an adduct with leucyl-tRNA in the editing site of the leucyl tRNA synthetase enzyme, occupying the amino acid binding pocket in the editing site. The trapping of this adduct in the editing site of leucyl-tRNA synthetase facilitates inhibition of the enzyme (Figure 3).
Advances and challenges in drug design against tuberculosis: application of in silico approaches
Published in Expert Opinion on Drug Discovery, 2019
Alexey Aleksandrov, Hannu Myllykallio
Gudzera et al. [65] proposed new inhibitors of Mtb leucyl-tRNA synthetase. Aminoacyl-tRNA synthetases catalyze attachment of amino acids to cognate tRNAs and are indispensable for protein synthesis. aatRNA synthetase structures have structural differences in prokaryotes and eukaryotes that can be exploited in the drug development. Gudzera et al. used the DOCK program to perform virtual screening of a library comprising around 100,000 molecules. The structure of Mtb LeuRS was modeled using the known Thermus thermophilus LeuRS structure as a structural template thanks to the high sequence similarity of 95% in residues comprising the active centers of these enzymes. The docking targeted the leucyl binding region in LeuRS active site. In vitro experiments revealed six compounds with inhibitory activity out 270 selected compounds. The compound with the best in vitro activity was used to retrieve additional 26 derivatives from the compound library. Three compounds out of nine tested demonstrated inhibitory activity against the Mtb H37Rv strain with a MIC of 25, 50, and 81 µM. In addition, the same authors identified the triazin-based molecules in the list of compound predicted by the in silico methods [66], which led to the discovery of compounds with IC50 of 7.6 µM and 7.2 µM against Mtb LeuRS.