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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The sequence of bases on the mRNA are organises as discrete triplet codes; three bases code for one amino acid, and different sequences of triplet bases, each called a codon, code for a particular amino acid. For example, GAC codes for the amino acid aspartic acid. The process of translation is not as straightforward as the amino acids lining up along the mRNA strand. A second type of RNA, called transfer-RNA, is involved. The tRNA is a smaller molecule and is responsible for binding free amino acids in the cytoplasm and bringing them to the mRNA template. The tRNA molecules contain an anticodon, which is the opposite sequence to that on the mRNA and is complementary, therefore the tRNA carrying the amino acid can bind to mRNA. Different codons are also present on the mRNA strand to determine where to start and terminate translation into a protein.
Translation
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
The strongest contribution of the RNA phage messengers was achieved, however, to the two-out-of-three reading hypothesis (Lagerkvist 1978). According to this hypothesis, a codon might be read by relying mainly on the Watson-Crick base pairs formed with the first two codon positions, while the mispaired nucleotides in the third codon and anticodon wobble positions make a comparatively small contribution to the total stability of the reading interaction. Thus, the MS2 RNA-dependent in vitro protein synthesis was used by the study on the differential utilization of leucyl-tRNAs in E. coli (Holmes et al. 1977). In parallel, the same system was employed by the codon-anticodon recognition studies in the valine codon family (Mitra et al. 1977). It was established that the three anticodons each recognized all four valine codons and concluded that the genetic code, as far as the valine codons were concerned, was operationally a two-letter code, i.e., the third codon nucleotide had no absolute discriminating function. With the MS2 RNA-programmed system, the relative efficiency of anticodons in reading the valine codons was investigated (Mitra et al. 1979). The MS2 RNA-programmed system was also employed to evaluate aberrations of the classical codon reading scheme during protein synthesis in vitro with alanine tRNAs (Samuelsson et al. 1980). Again, each of the anticodons was able to read all four alanine codons, but under conditions of no competition.
Mitochondrial DNAs and Phylogenetic Relationships
Published in S. K. Dutta, DNA Systematics, 2019
Detailed nucleotide sequence analysis of mtDNA has also revealed several interesting features, but perhaps the most surprising of these is the observation that the mitochondrion does not utilize the universal genetic code, and moreover that the code used varies somewhat from organism to organism. In the mitochondrial code more groups of four codons can be read by a single tRNA. The tRNAs which correspond to these four-codon families have a U in the first anticodon position which, in the unmodified form, can pair with any of the four bases which may be present in the third position of the codon.79–82 As a consequence, fewer tRNAs are required in the mitochondrion than for the universal code and 22 different tRNAs were found in mammalian mitochondria,67–70 24 in yeast,81 and 23 in Neurospora.83,84 Mitochondrial tRNAs have many features which distinguish them from their cytoplasmic counterparts. It has been proposed that in mammals, the presence of a modified nucleotide in the position immediately 3′ to the anticodon restricts the codon recognition response to U or G “wobble”83 only, whereas its absence would permit U, C, A, or G wobble, thus resulting in a four-codon family.82
Isolation of monoclonal antibodies from anti-synthetase syndrome patients and affinity maturation by recombination of independent somatic variants
Published in mAbs, 2020
Luke Burman, Yeeting E. Chong, Sherie Duncan, Anders Klaus, Kaitlyn Rauch, Kristina Hamel, Karine Hervé, Stephanie Pfaffen, David W. Collins, Kevin Heyries, Leslie Nangle, Carl Hansen, David J. King
Histidyl-tRNA synthetase (HARS) is one of a number of aminoacyl-tRNA synthetases that have additional functions outside of protein synthesis, with both intracellular and extracellular non-canonical functions reported.22–25 Several aminoacyl-tRNA synthetases, including HARS as well as splice variants from their genes, are secreted and have potentially important roles in regulation of the immune system.26–29 Monoclonal antibodies to HARS are, therefore, of interest for their potential ability to regulate the immune system. The rare human autoimmune disease, Jo-1 positive anti-synthetase syndrome (ASS), is characterized by the presence of autoantibodies to HARS.30 These autoantibodies remove free HARS from the circulation and are associated with individuals exhibiting activated immune pathology.29 The HARS protein can be divided into three domains: 1) an N-terminal coiled-coil WHEP domain, 2) a central catalytic domain, and 3) a C-terminal anticodon binding domain (ABD). Autoantibodies have been reported to most frequently recognize epitopes within the N- or C-terminal domains.26 In this study, we set out to isolate human monoclonal antibodies to HARS from Jo-1 positive individuals, and to investigate the generation of high-affinity antibodies using the information available in related sequences.
Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation
Published in OncoImmunology, 2018
Isabell Adam, Dyah L. Dewi, Joram Mooiweer, Ahmed Sadik, Soumya R. Mohapatra, Bianca Berdel, Melanie Keil, Jana K. Sonner, Kathrin Thedieck, Adam J. Rose, Michael Platten, Ines Heiland, Saskia Trump, Christiane A. Opitz
In contrast to WARS, mitochondrial WARS2 did not correlate with IDO1 or TDO2 (Figure 1A; Figure2B) and was regulated neither by IFNγ (Figure 1E)39 nor by GCN2-peIF2a-ATF4 signaling (Figure 4D and H). Both WARS and WARS2 belong to the class I aminoacyl-tRNA synthetases, which contain a characteristic Rossman fold catalytic domain39. However, WARS2 only aligns to the carboxyl-terminal part of WARS and thus the two enzymes only share 11% sequence identity39. The two TrpRS bind tRNAs with different anticodons. WARS2 binds mitochondrial tRNATrp with the anticodon UCA, which codes for Trp in the mitochondria of humans40, while WARS binds cytoplasmic tRNATrp, which contains the standard anticodon CCA. Little is known about free Trp concentrations in mitochondria and it is therefore not clear how mitochondrial Trp concentrations are affected by Trp depletion. Our results reveal that Trp starvation, which most strongly induces WARS, generally appears to upregulate the expression of cytoplasmic rather than mitochondrial tRNA synthetases (Figure 4O).
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
Transfer RNAs couple with mRNA and ferry the amino acids composing the proteins. Anticodon-engineered suppressor tRNAs may be beneficial to patients with CF bearing nonsense mutations. They are designed to carry a nonsense suppressing anticodon to address PTCs and to introduce the correct amino acid to the elongating peptide [52]. This approach has been implemented successfully in vitro with readthrough of stop codons in CF airway epithelial cells [53]. It has the advantage of incorporating the correct amino acid leading to a normal functional protein. However, suppressor tRNAs are macromolecules that are not readily taken up by cells and they require effective delivery technologies. Their evaluation is at the preclinical stage (Table 1).