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Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Translation is done at organelles called ribosomes. A ribosome attaches to the starting codon on the mRNA molecule. A tRNA molecule, with a complementary anticodon, carries a specific amino acid and attaches to the mRNA by specific base pairing. A second tRNA molecule attaches to the next codon in the sequence in the same way. The ribosome moves along the mRNA molecule, working on two tRNA molecules at a time, and joins together the two amino acids via a peptide bond, using an enzyme and ATP. As the ribosome continues to move along the mRNA stand, the free tRNA molecules break loose and departs to collect another of the same amino acid from the pool of amino acids in the cytoplasm. This process continues until the ribosome reaches a stop codon (one that does not code for an amino acid) and the completed peptide is released. Note that up to 50 ribosomes can pass immediately after the first, so many identical polypeptides can be synthesised simultaneously. It is at this point that the tertiary structure would assemble from its constituent polypeptides.
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
Leading edge: emerging drug, cell, and gene therapies for junctional epidermolysis bullosa
Published in Expert Opinion on Biological Therapy, 2020
Allison R. Keith, Kirk Twaroski, Christen L. Ebens, Jakub Tolar
Gentamicin is a broad-spectrum aminoglycoside antibiotic approved for the treatment of Gram-negative bacterial infections that has recently demonstrated efficacy in promoting readthrough of premature termination codons (PTCs) to restore full-length, functional proteins in EB [41–43]. Gentamicin promotes PTC readthrough by interfering with two adenosines, A1755 and A1756, on helix 44 of the 18 S ribosomal RNA in the 40 S subunit of eukaryotic ribosomes [44]. By flipping these two adenosines outward, gentamicin alters the decoding center that ensures the accurate selection of aminoacyl-transfer RNAs (tRNAs) corresponding with mRNA codons. Gentamicin–ribosome interactions lead to decreased codon-anticodon recognition at the aminoacyl-tRNA acceptor site, which allows for the incorporation of near-cognate aminoacyl-tRNAs at the location of PTCs [45]. Efficiency of gentamicin-induced PTC readthrough is determined by the type of stop codon and sequence (UAA, UAG, or UGA). A recent investigation demonstrated that UGA stop codons result in higher levels of readthrough than UAG and UAA stop codons, respectively [45]. Additionally, a cytosine at the +4 position and a uracil at the −1 position are significantly linked to enhance gentamicin-induced readthrough response [45]. This evidence may narrow participant selection criteria for clinical trials focused on drug-induced PTC readthrough.
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.
Mitochondrial tRNAAla C5601T mutation may modulate the clinical expression of tRNAMet A4435G mutation in a Han Chinese family with hypertension
Published in Clinical and Experimental Hypertension, 2018
Ping Zheng, Shiliang Li, Chun Liu, Zhengbiao Zha, Xiang Wei, Yuan Yuan
Sequence analysis of the complete mt-tRNA genes in matrilineal relatives of this family showed the presence of A4435G mutation in tRNAMet and C5601T mutation in tRNAAla genes (Figures 2 and 3). The well-known A4435G mutation was located immediately at the 3 prime end to the anticodon, corresponding with the conventional position 37 of the tRNAMet (18). In fact, an adenine at this position was an extraordinarily conserved base in every sequenced methionine tRNA from bacteria to human mitochondria (19). Almost all of the A37 in tRNAs are modified, e.g., thiolation and methylation (20). Indeed, this modified nucleotide contributes to the high fidelity of codon recognition, as well as the structural formation and stabilization of functional tRNAs (21). A previous study showed that compared with a control cell lacking the mutation, ~40% reduction in the levels of tRNAMet was observed in cells carrying the A4435G mutation (22). The lower levels of tRNAMet in cells carrying the A4435G mutation most probably result from a defect in nucleotide modification at position 37 of tRNAMet. As a result, a shortage of the tRNAMet is responsible for the reduced rate of mitochondrial protein synthesis.