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Translation and Post-Translational Modifications During Aging
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
The function of a tRNA in transferring the amino acid to the ribosome-mRNA complex is dependent upon a specific enzyme that catalyzes the ligation of the appropriate amino acid to its acceptor arm at the 3′ end. This process, aminoacylation of a tRNA, is also known as “charging”, and the enzymes involved in this process are called aminoacyl-tRNA synthetases (aaRS) or, more accurately, aminoacyl-tRNA ligases. A group of isoaccepting tRNAs are charged only by the single aaRS specific for their amino acid.69
Mupirocin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Antibacterial activity of P. fluorescens was first recorded in 1887 by Baader and Garre (quoted by Casewell and Hill, 1985), but it was not until 1971 that Fuller et al. isolated mupirocin, the major metabolite that accounted for most of this activity (Fuller et al., 1971; Casewell and Hill, 1985; Baader and Garre, 1887). Mupirocin contains the biogenetically unique 9-hydroxy-nonanoic acid moiety, a molecule that has some resemblance to isoleucyl and binds reversibly to the class I isoleucyl–tRNA synthetase from several eubacteria (Chain and Mellows, 1977; Alexander et al., 1978; Hughes and Mellows, 1980). The synthetase is responsible for the formation of isoleucyl–tRNA by means of the aminoacylation of isoleucine to the cognate tRNA.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Aminoacyl-tRNA synthetases are well-validated parasite drug targets (Kalidas et al. 2014, Pham et al. 2014). Having previously solved X-ray crystal structures of T. cruzi histidyl-tRNA synthetase (TcHisRS), T. brucei HisRS, and human cytosolic HisRS (Merritt et al. 2010, Koh et al. 2014), and identified trypanosomal-specific pockets (Koh et al. 2014), Koh et al. (2015) sought to identify chemical starting points for parasite-selective HisRS inhibitors by performing an X-ray crystallographic fragment screen of the Medical Structural Genomics of Pathogenic Protozoa (MSGPP) fragment library. Histidine-complexed TcHisRS crystals were soaked with 68 different fragment cocktails of ten fragments each. Co-crystal structures were solved for fifteen fragments (2.2% hit rate), and all fifteen fragments were observed to bind to the same site—a narrow groove adjacent to the histidine binding site that is not present in the crystal structure without the fragments bound. The site is in very close proximity to the binding site of the adenine ring of the histidyl-AMP reaction intermediate and it is likely that fragment binding will interfere with ATP/histidyl-AMP binding. Although fragment binding was observed by X-ray crystallography, binding of only one of the fifteen fragments could be detected by DSF, when fragments were tested at 1 mM. Additionally, the fragments showed little inhibitory activity in an aminoacylation assay; at a concentration of 2 mM, the most active fragments (including the fragment that gave rise to a thermal shift in the DSF assay) inhibited aminoacylation by 20–39%.
Roux-en-Y gastric bypass and sleeve gastrectomy induce substantial and persistent changes in microbial communities and metabolic pathways
Published in Gut Microbes, 2022
Jerry T. Dang, Valentin Mocanu, Heekuk Park, Michael Laffin, Naomi Hotte, Shahzeer Karmali, Daniel W. Birch, Karen L. Madsen
These effects may be mediated through the aa-tRNA biosynthesis pathway, which was enriched in both microbial and metabolic functional analysis. After SG, this pathway is driven by increases in five amino acids that were associated with a reduction in the abundance of BEM bacteria. tRNAs are formed by direct aminoacylation of tRNAs, which are catalyzed by aminoacyl-tRNA synthetases (aaRS).28 Alterations in tRNA biology have been associated with metabolic disorders.29 Specifically, mutations in aaRSs and variants of the tRNA-modifying enzyme CDKAL1 have been associated with an increased risk of obesity and type 2 diabetes.30–32 Mutations in mitochondrial tRNA genes have also been associated with maternally inherited diabetes,33 while mutations in tRNA methyltransferase TRMT10A directly cause young-onset diabetes.34 aaRSs are also involved in intracellular amino acid signaling and recent studies support the notion that depletion or enrichment of amino acids modulate the activity of aa-tRNA biosynthesis.35 Given the findings of our study, it is plausible that the loss of the BEM Firmicutes cluster encourages the production of amino acids, which concomitantly enrich the aa-tRNA biosynthesis pathway. Furthermore, this enrichment potentiates improved glucose, lower weight, and decreased systemic inflammation.
The role of antibody delivery formation in cancer therapy
Published in Journal of Drug Targeting, 2020
Tongtong Qi, Yanbin Shi, Yi Huang, Xianglei Fu, Shengnan Qiu, Qifeng Sun, Guimei Lin
Chemical aminoacylation can insert unnatural amino acids into proteins that require modification for application in disease diagnosis and treatment [83–87]. Feng et al. used anti-5T4 and anti-Her2 antibodies as model systems for cleavable or non-cleavable monomethyl lauryl imide-D and protease by incorporating ketone and hydroxylamine functionalised on the side chain of the unnatural amino acid. A cleavage bond is formed between the linkers to generate a site-specific antibody drug conjugate (NDC). These conjugates are highly stable and show in rodent models relative to conventional antibody drug conjugates conjugated to engineered surface exposed or reduced interchain disulphide cysteine residues, thus exhibiting improved in vitro and in vivo efficacy and pharmacokinetic stability [70,79,88].
Fragment-based screening with natural products for novel anti-parasitic disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
A similar study using crystallographic fragment screening was undertaken to find potential inhibitors of T. cruzi histidyltRNA synthetase (HisRS) [42]. Sixty-eight fragment cocktails were generated from 680 commercially available fragments by mixing 10 compounds into one cocktail. Crystallographic fragment screening of 68 cocktails with TcHisRS*His crystals has identified 15 cocktails containing putative hits. Subsequent confirmation screening was performed by single soaking of all of the candidate fragments and 15 single fragments (53–67) (Figure 12) were confirmed as binders. All 15 fragments were found to bind to the same binding site of TcHisRS*His, with one of the fragments (55) occupying a second binding site with lower affinity. Thermal shift assay was applied to all 15 hits, but only one fragment (54) showed thermal stabilization effect of TcHisRS*His by about 1.6 ℃. Three fragment binders (54, 55, 59) were found to have weak inhibition activity (20%, 21%, and 39%) in the aminoacylation assay at concentration of 2 mM.