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https://www.readbyqxmd.com/read/28934368/a-single-danio-rerio-hars-gene-encodes-both-cytoplasmic-and-mitochondrial-histidyl-trna-synthetases
#1
Ashley L Waldron, Sara Helms Cahan, Christopher S Franklyn, Alicia M Ebert
Histidyl tRNA Synthetase (HARS) is a member of the aminoacyl tRNA synthetase (ARS) family of enzymes. This family of 20 enzymes is responsible for attaching specific amino acids to their cognate tRNA molecules, a critical step in protein synthesis. However, recent work highlighting a growing number of associations between ARS genes and diverse human diseases raises the possibility of new and unexpected functions in this ancient enzyme family. For example, mutations in HARS have been linked to two different neurological disorders, Usher Syndrome Type IIIB and Charcot Marie Tooth peripheral neuropathy...
2017: PloS One
https://www.readbyqxmd.com/read/28933646/visualizing-trna-dependent-mistranslation-in-human-cells
#2
Jeremy T Lant, Matthew D Berg, Daniel Hw Sze, Kyle S Hoffman, Ibukunoluwa C Akinpelu, Matthew Turk, Ilka U Heinemann, Martin L Duennwald, Christopher J Brandl, Patrick O'Donoghue
High-fidelity translation and a strictly accurate proteome were originally assumed as essential to life and cellular viability. Yet recent studies in bacteria and eukaryotic model organisms suggest that proteome-wide mistranslation can provide selective advantages and is tolerated in the cell at higher levels than previously thought (one error in 6.9 × 10(-4) in yeast) with a limited impact on phenotype. Previously, we selected a tRNA(Pro) containing a single mutation that induces mistranslation with alanine at proline codons in yeast...
September 21, 2017: RNA Biology
https://www.readbyqxmd.com/read/28924459/genetic-code-optimization-for-cotranslational-protein-folding-codon-directional-asymmetry-correlates-with-antiparallel-betasheets-trna-synthetase-classes
#3
Hervé Seligmann, Ganesh Warthi
A new codon property, codon directional asymmetry in nucleotide content (CDA), reveals a biologically meaningful genetic code dimension: palindromic codons (first and last nucleotides identical, codon structure XZX) are symmetric (CDA = 0), codons with structures ZXX/XXZ are 5'/3' asymmetric (CDA = - 1/1; CDA = - 0.5/0.5 if Z and X are both purines or both pyrimidines, assigning negative/positive (-/+) signs is an arbitrary convention). Negative/positive CDAs associate with (a) Fujimoto's tetrahedral codon stereo-table; (b) tRNA synthetase class I/II (aminoacylate the 2'/3' hydroxyl group of the tRNA's last ribose, respectively); and (c) high/low antiparallel (not parallel) betasheet conformation parameters...
2017: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/28918092/growth-rate-dependent-regulation-of-trna-level-and-charging-in-bacillus-licheniformis
#4
Iolanda Ferro, Klaus Liebeton, Zoya Ignatova
Cellular growth crucially depends on protein synthesis and the abundance of translational components. Among them, aminoacyl-tRNAs play a central role in biosynthesis and shape the kinetics of mRNA translation, thus influencing protein production. Here, we used microarray-based approaches to determine the charging levels and tRNA abundance of Bacillus licheniformis. We observed an interesting cross-talk among tRNA expression, charging pattern and growth rate. For a large subset of tRNAs, we found a co-regulated and augmented expression at high growth rate...
September 13, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28910581/aminoacyl-trna-quality-control-is-required-for-efficient-activation-of-the-tor-pathway-regulator-gln3p
#5
Kyle Mohler, Rebecca Mann, Amanda Kyle, Noah Reynolds, Michael Ibba
The aminoacylation status of the cellular tRNA pool regulates both general amino acid control (GAAC) and target of rapamycin (TOR) stress response pathways in yeast. Consequently, fidelity of translation at the level of aminoacyl-tRNA synthesis plays a central role in determining accuracy and sensitivity of stress responses. To investigate effects of translational quality control (QC) on cell physiology under stress conditions, phenotypic microarray analyses were used to identify changes in QC deficient cells...
September 14, 2017: RNA Biology
https://www.readbyqxmd.com/read/28910101/anisotropic-fluctuations-in-the-ribosome-determine-trna-kinetics
#6
Huan Yang, Jeffrey K Noel, Paul Charles Whitford
The ribosome is a large ribonucleoprotein complex that is responsible for the production of proteins in all organisms. Accommodation is the process by which an incoming aminoacyl-transfer RNA (aa-tRNA) molecule binds the ribosomal A site, and its kinetics has been implicated in the accuracy of tRNA selection. In addition to rearrangements in the aa-tRNA molecule, the L11 stalk can undergo large-scale anisotropic motions during translation. To explore the potential impact of this protruding region on the rate of aa-tRNA accommodation, we used molecular dynamics simulations with a simplified model to evaluate the free energy as a function of aa-tRNA position...
September 14, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28905505/biallelic-variants-in-wars2-encoding-mitochondrial-tryptophanyl-trna-synthase-in-six-individuals-with-mitochondrial-encephalopathy
#7
Saskia B Wortmann, Sharita Timal, Hanka Venselaar, Liesbeth T Wintjes, Robert Kopajtich, René G Feichtinger, Carla Onnekink, Mareike Mühlmeister, Ulrich Brandt, Jan A Smeitink, Joris A Veltman, Wolfgang Sperl, Dirk Lefeber, Ger Pruijn, Vesna Stojanovic, Peter Freisinger, Francjan V Spronsen, Terry Gj Derks, Hermine E Veenstra-Knol, Johannes A Mayr, Agnes Rötig, Mark Tarnopolsky, Holger Prokisch, Richard J Rodenburg
Mitochondrial protein synthesis involves an intricate interplay between mitochondrial DNA encoded RNAs and nuclear DNA encoded proteins, such as ribosomal proteins and aminoacyl-tRNA synthases. Eukaryotic cells contain 17 mitochondria-specific aminoacyl-tRNA synthases. WARS2 encodes mitochondrial tryptophanyl-tRNA synthase (mtTrpRS), a homodimeric class Ic enzyme (mitochondrial tryptophan-tRNA ligase; EC 6.1.1.2). Here, we report six individuals from five families presenting with either severe neonatal onset lactic acidosis, encephalomyopathy and early death or a later onset, more attenuated course of disease with predominating intellectual disability...
September 14, 2017: Human Mutation
https://www.readbyqxmd.com/read/28905057/a-water-mediated-and-substrate-assisted-aminoacylation-mechanism-in-the-discriminating-aminoacyl-trna-synthetase-glnrs-and-non-discriminating-glurs
#8
Mohamed M Aboelnga, John J Hayward, James W Gauld
Glutaminyl-tRNA synthetase (GlnRS) catalyzes the aminoacylation of glutamine to the corresponding tRNA(Gln). However, most bacteria and all archaea lack GlnRS and thus an indirect noncanonical aminoacylation is required. With the assistance of a non-discriminating version of Glutamyl-tRNA synthetases (ND-GluRS) the tRNA(Gln) is misaminoacylated by glutamate. In this study, we have computationally investigated the aminoacylation mechanism in GlnRS and ND-GluRS employing Molecular Dynamics (MD) simulations, Quantum Mechanics (QM) cluster and Quantum Mechanics/Molecular Mechanics (QM/MM) calculations...
September 14, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28903058/insuperable-problems-of-the-genetic-code-initially-emerging-in-an-rna-world
#9
Peter R Wills, Charles W Carter
Differential equations for error-prone information transfer (template replication, transcription or translation) are developed in order to consider, within the theory of autocatalysis, the advent of coded protein synthesis. Variations of these equations furnish a basis for comparing the plausibility of contrasting scenarios for the emergence of specific tRNA aminoacylation, ultimately by enzymes, and the relationship of this process with the origin of the universal system of molecular biological information processing embodied in the Central Dogma...
September 10, 2017: Bio Systems
https://www.readbyqxmd.com/read/28902227/a-genetically-encoded-cyclobutene-probe-for-labelling-of-live-cells
#10
K Liu, B Enns, B Evans, N Wang, X Shang, W Sittiwong, P H Dussault, J Guo
We have identified an aminoacyl-tRNA synthetase/tRNA pair for the efficient and site-specific incorporation of a cyclobutene-containing amino acid into proteins in response to an amber nonsense codon. Fast and fluorescent labeling of purified proteins and intact proteins in live cells was demonstrated using the inverse electron demand Diels-Alder reaction with a tetrazine.
September 21, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28901837/minimal-requirements-for-reverse-polymerization-and-trna-repair-by-trna-his-guanylyltransferase
#11
Riddhi Desai, Kunmo Kim, Hanna C Buechsenschuetz Allan W Chen, Yumin Bi, Mitchell R Mann, Matthew A Turk, Christina Z Chung, Ilka U Heinemann
tRNA(His) guanylyltransferase (Thg1) has unique reverse (3'-5') polymerase activity occurring in all three domains of life. Most eukaryotic Thg1 homologs are essential genes involved in tRNA(His) maturation. These enzymes normally catalyze a single 5' guanylation of tRNA(His) lacking the essential G(-1) identity element required for aminoacylation. Recent studies suggest that archaeal type Thg1, which includes most archaeal and bacterial Thg1 enzymes is phylogenetically distant from eukaryotic Thg1. Thg1 is evolutionarily related to canonical 5'-3' forward polymerases but catalyzes reverse 3'-5'polymerization...
September 13, 2017: RNA Biology
https://www.readbyqxmd.com/read/28887846/mutations-in-kars-cause-early-onset-hearing-loss-and-leukoencepha-lopathy-potential-pathogenic-mechanism
#12
Xiao-Long Zhou, Long-Xia He, Li-Jia Yu, Yong Wang, Xi-Jin Wang, En-Duo Wang, Tao Yang
Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remain unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next-generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl-tRNA synthetase (LysRS), as the only candidate causative variants...
September 8, 2017: Human Mutation
https://www.readbyqxmd.com/read/28880538/characterization-of-the-functional-variance-in-mbth-like-protein-interactions-with-a-nonribosomal-peptide-synthetase
#13
Rebecca A Schomer, Michael G Thomas
Many nonribosomal peptide synthetases (NRPSs) require MbtH-like proteins (MLPs) for solubility or for activation of amino acid substrate by the adenylation domain. MLPs are capable of functional crosstalk with noncognate NRPSs at varying levels. Using enterobactin biosynthesis in Escherichia coli as a model MLP-dependent NRPS system, we use in vivo and in vitro techniques to characterize how seven noncognate MLPs influence the function of the enterobactin NRPS EntF when the cognate MLP, YbdZ, is absent. Using a series of in vitro assays to analyze EntF solubility, adenylation, aminoacylation, and in vitro enterobactin production, we show that interactions between MLPs and NRPSs are multifaceted and more complex than previously appreciated...
September 20, 2017: Biochemistry
https://www.readbyqxmd.com/read/28875841/new-molecular-targets-and-strategies-for-antimalarial-discovery
#14
Anna Caroline Aguiar, Lorena R F de Sousa, Celia R S Garcia, Glaucius Oliva, Rafael V C Guido
Malaria remains a major health problem, especially because of the emergence of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and affordable antimalarial drugs are desperately needed. New proteins have been investigated as molecular targets for research and development of innovative compounds with well-defined mechanism of action. In this review, we highlight genetically and clinically validated plasmodial proteins as drug targets for the next generation of therapeutics. The enzymes described herein are involved in hemoglobin hydrolysis, the invasion process, elongation factors for protein synthesis, pyrimidine biosynthesis, post-translational modifications such as prenylation, phosphorylation and histone acetylation, generation of ATP in mitochondrial metabolism and aminoacylation of RNAs...
August 29, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28875178/genetic-validation-of-leishmania-donovani-lysyl-trna-synthetase-shows-that-it-is-indispensable-for-parasite-growth-and-infectivity
#15
Sanya Chadha, N Arjunreddy Mallampudi, Debendra K Mohapatra, Rentala Madhubala
Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis. Increasing resistance and severe side effects of existing drugs have led to the need to identify new chemotherapeutic targets. Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous and are required for protein synthesis. aaRSs are known drug targets for bacterial and fungal pathogens. Here, we have characterized and evaluated the essentiality of L. donovani lysyl-tRNA synthetase (LdLysRS). Two different coding sequences for lysyl-tRNA synthetases are annotated in the Leishmania genome database...
July 2017: MSphere
https://www.readbyqxmd.com/read/28872118/quantification-of-the-abundance-and-charging-levels-of-transfer-rnas-in-escherichia-coli
#16
Thomas Søndergaard Stenum, Michael A Sørensen, Sine Lo Svenningsen
Transfer RNA (tRNA) is an essential part of the translational machinery in any organism. tRNAs bind and transfer amino acids to the translating ribosome. The relative levels of different tRNAs, and the ratio of aminoacylated tRNA to total tRNA, known as the charging level, are important factors in determining the accuracy and speed of translation. Therefore, the abundance and charging levels of tRNAs are important variables to measure when studying protein synthesis, for example under various stress conditions...
August 22, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28853922/origin-and-evolution-of-the-universal-genetic-code
#17
Eugene V Koonin, Artem S Novozhilov
The standard genetic code (SGC) is virtually universal among extant life forms. Although many deviations from the universal code exist, particularly in organelles and prokaryotes with small genomes, they are limited in scope and obviously secondary. The universality of the code likely results from the combination of a frozen accident, i.e., the deleterious effect of codon reassignment in the SGC, and the inhibitory effect of changes in the code on horizontal gene transfer. The structure of the SGC is nonrandom and ensures high robustness of the code to mutational and translational errors...
August 30, 2017: Annual Review of Genetics
https://www.readbyqxmd.com/read/28837402/trna-pyl-structure-function-and-applications
#18
Jeffery M Tharp, Andreas Ehnbom, Wenshe R Liu
Pyrrolysine is the 22(nd) proteinogenic amino acid encoded into proteins in response to amber (TAG) codons in a small number of archaea and bacteria. The incorporation of pyrrolysine is facilitated by a specialized aminoacyl-tRNA synthetase (PylRS) and its cognate tRNA (tRNA(Pyl)). The secondary structure of tRNA(Pyl) contains a number of unique features not found in canonical tRNAs. Numerous studies have demonstrated that the PylRS/tRNA(Pyl) pair from archaea is orthogonal in E. coli and eukaryotic hosts, which has led to the widespread use of this pair for the genetic incorporation of non-canonical amino acids...
August 24, 2017: RNA Biology
https://www.readbyqxmd.com/read/28836574/translational-fidelity-and-mistranslation-in-the-cellular-response-to-stress
#19
REVIEW
Kyle Mohler, Michael Ibba
Faithful translation of mRNA into the corresponding polypeptide is a complex multistep process, requiring accurate amino acid selection, transfer RNA (tRNA) charging and mRNA decoding on the ribosome. Key players in this process are aminoacyl-tRNA synthetases (aaRSs), which not only catalyse the attachment of cognate amino acids to their respective tRNAs, but also selectively hydrolyse incorrectly activated non-cognate amino acids and/or misaminoacylated tRNAs. This aaRS proofreading provides quality control checkpoints that exclude non-cognate amino acids during translation, and in so doing helps to prevent the formation of an aberrant proteome...
August 24, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28828732/coding-of-class-i-and-ii-aminoacyl-trna-synthetases
#20
Charles W Carter
The aminoacyl-tRNA synthetases and their cognate transfer RNAs translate the universal genetic code. The twenty canonical amino acids are sufficiently diverse to create a selective advantage for dividing amino acid activation between two distinct, apparently unrelated superfamilies of synthetases, Class I amino acids being generally larger and less polar, Class II amino acids smaller and more polar. Biochemical, bioinformatic, and protein engineering experiments support the hypothesis that the two Classes descended from opposite strands of the same ancestral gene...
August 22, 2017: Advances in Experimental Medicine and Biology
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