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tRNA Synthetase

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https://www.readbyqxmd.com/read/28335420/efforts-and-challenges-in-engineering-the-genetic-code
#1
REVIEW
Xiao Lin, Allen Chi Shing Yu, Ting Fung Chan
This year marks the 48th anniversary of Francis Crick's seminal work on the origin of the genetic code, in which he first proposed the "frozen accident" hypothesis to describe evolutionary selection against changes to the genetic code that cause devastating global proteome modification. However, numerous efforts have demonstrated the viability of both natural and artificial genetic code variations. Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome...
March 14, 2017: Life
https://www.readbyqxmd.com/read/28328135/confirmation-of-cagsss-syndrome-as-a-distinct-entity-in-a-danish-patient-with-a-novel-homozygous-mutation-in-iars2
#2
Shahida Moosa, Annette Haagerup, Pernille Axel Gregersen, Karin Kastberg Petersen, Janine Altmüller, Holger Thiele, Peter Nürnberg, Tae-Joon Cho, Ok-Hwa Kim, Gen Nishimura, Bernd Wollnik, Ida Vogel
Since the original description of the IARS2-related cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia syndrome (CAGSSS; OMIM 616007) in an extended consanguineous family of French-Canadian descent, no further patients have been reported. IARS2 (OMIM 612801) encodes the mitochondrial isoleucine-tRNA synthetase which belongs to the class-I aminoacyl-tRNA synthetase family, and has been implicated in CAGSSS and a form of Leigh syndrome. Here, we report on a female Danish patient with a novel homozygous IARS2 mutation, p...
April 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28321488/evolutionary-gain-of-highly-divergent-trna-specificities-by-two-isoforms-of-human-histidyl-trna-synthetase
#3
Yi-Hsueh Lee, Chia-Pei Chang, Yu-Ju Cheng, Yi-Yi Kuo, Yeong-Shin Lin, Chien-Chia Wang
The discriminator base N73 is a key identity element of tRNA(His). In eukaryotes, N73 is an "A" in cytoplasmic tRNA(His) and a "C" in mitochondrial tRNA(His). We present evidence herein that yeast histidyl-tRNA synthetase (HisRS) recognizes both A73 and C73, but somewhat prefers A73 even within the context of mitochondrial tRNA(His). In contrast, humans possess two distinct yet closely related HisRS homologues, with one encoding the cytoplasmic form (with an extra N-terminal WHEP domain) and the other encoding its mitochondrial counterpart (with an extra N-terminal mitochondrial targeting signal)...
March 20, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28318058/nuclear-codon-reassignments-in-the-genomics-era-and-mechanisms-behind-their-evolution
#4
REVIEW
Martin Kollmar, Stefanie Mühlhausen
The canonical genetic code ubiquitously translates nucleotide into peptide sequence with several alterations known in viruses, bacteria, mitochondria, plastids, and single-celled eukaryotes. A new hypothesis to explain genetic code changes, termed tRNA loss driven codon reassignment, has been proposed recently when the polyphyly of the yeast codon reassignment events has been uncovered. According to this hypothesis, the driving force for genetic code changes are tRNA or translation termination factor loss-of-function mutations or loss-of-gene events...
March 20, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28317434/dynamics-of-the-active-site-loops-in-catalyzing-aminoacylation-reaction-in-seryl-and-histidyl-trna-synthetases
#5
Saheb Dutta, Soumya Kundu, Amrita Saha, Nilashis Nandi
Aminoacylation reaction is the first step of protein biosynthesis. The catalytic reorganization at the active site of aminoacyl tRNA synthetases (aaRSs) is driven by the loop motions. There remain lacunae of understanding concerning the catalytic loop dynamics in aaRSs. We analyzed the functional loop dynamics in seryl tRNA synthetase from Methanopyrus kandleri ((mk)SerRS) and histidyl tRNA synthetases from Thermus thermophilus ((tt)HisRS), respectively, using molecular dynamics. Results confirm that the motif 2 loop and other active site loops are flexible spots within the catalytic domain...
March 20, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28303005/ligand-co-crystallization-of-aminoacyl-trna-synthetases-from-infectious-disease-organisms
#6
Spencer O Moen, Thomas E Edwards, David M Dranow, Matthew C Clifton, Banumathi Sankaran, Wesley C Van Voorhis, Amit Sharma, Colin Manoil, Bart L Staker, Peter J Myler, Donald D Lorimer
Aminoacyl-tRNA synthetases (aaRSs) charge tRNAs with their cognate amino acid, an essential precursor step to loading of charged tRNAs onto the ribosome and addition of the amino acid to the growing polypeptide chain during protein synthesis. Because of this important biological function, aminoacyl-tRNA synthetases have been the focus of anti-infective drug development efforts and two aaRS inhibitors have been approved as drugs. Several researchers in the scientific community requested aminoacyl-tRNA synthetases to be targeted in the Seattle Structural Genomics Center for Infectious Disease (SSGCID) structure determination pipeline...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28293456/acute-digital-ischemia-a-rare-presentation-of-antisynthetase-syndrome
#7
Jin Ei Chan, Sandeep Palakodeti, Matthew J Koster
Antisynthetase syndrome (ASS) is recognized as a subgroup of idiopathic inflammatory myopathies (IIMs). It is associated with autoantibodies directed against aminoacyl-transfer ribonucleic acid (tRNA) synthetase enzymes. We report the first case of anti-PL-7/anti-SSA 52kD ASS presenting as acute digital ischemia, an association not described previously. Occlusive vasculopathy is a rare but serious manifestation that can be seen at presentation in patients with ASS and may herald the onset of severe interstitial lung disease (ILD)...
March 2017: European Journal of Rheumatology
https://www.readbyqxmd.com/read/28289692/augmenting-the-anisotropic-network-model-with-torsional-potentials-improves-path-performance-enabling-detailed-comparison-with-experimental-rate-data
#8
Srinivas Niranj Chandrasekaran, Charles W Carter
PATH algorithms for identifying conformational transition states provide computational parameters-time to the transition state, conformational free energy differences, and transition state activation energies-for comparison to experimental data and can be carried out sufficiently rapidly to use in the "high throughput" mode. These advantages are especially useful for interpreting results from combinatorial mutagenesis experiments. This report updates the previously published algorithm with enhancements that improve correlations between PATH convergence parameters derived from virtual variant structures generated by RosettaBackrub and previously published kinetic data for a complete, four-way combinatorial mutagenesis of a conformational switch in Tryptophanyl-tRNA synthetase...
May 2017: Structural Dynamics (Melville, N.Y.)
https://www.readbyqxmd.com/read/28288813/a-genomically-modified-escherichia-coli-strain-carrying-an-orthogonal-e-coli-histidyl-trna-synthetase%C3%A2-trna-his-pair
#9
Markus Englert, Oscar Vargas-Rodriguez, Noah M Reynolds, Yane-Shih Wang, Dieter Söll, Takuya Umehara
BACKGROUND: Development of new aminoacyl-tRNA synthetase (aaRS)•tRNA pairs is central for incorporation of novel non-canonical amino acids (ncAAs) into proteins via genetic code expansion (GCE). The Escherichia coli and Caulobacter crescentus histidyl-tRNA synthetases (HisRS) evolved divergent mechanisms of tRNA(His) recognition that prevent their cross-reactivity. Although the E. coli HisRS•tRNA(His) pair is a good candidate for GCE, its use in C. crescentus is limited by the lack of established genetic selection methods and by the low transformation efficiency of C...
March 10, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28287455/biosynthesis-of-sulfur-containing-trna-modifications-a-comparison-of-bacterial-archaeal-and-eukaryotic-pathways
#10
REVIEW
Mirela Čavužić, Yuchen Liu
Post-translational tRNA modifications have very broad diversity and are present in all domains of life. They are important for proper tRNA functions. In this review, we emphasize the recent advances on the biosynthesis of sulfur-containing tRNA nucleosides including the 2-thiouridine (s²U) derivatives, 4-thiouridine (s⁴U), 2-thiocytidine (s²C), and 2-methylthioadenosine (ms²A). Their biosynthetic pathways have two major types depending on the requirement of iron-sulfur (Fe-S) clusters. In all cases, the first step in bacteria and eukaryotes is to activate the sulfur atom of free l-cysteine by cysteine desulfurases, generating a persulfide (R-S-SH) group...
March 11, 2017: Biomolecules
https://www.readbyqxmd.com/read/28276441/rna-surveillance-via-nonsense-mediated-mrna-decay-is-crucial-for-longevity-in-daf-2-insulin-igf-1-mutant-c-elegans
#11
Heehwa G Son, Mihwa Seo, Seokjin Ham, Wooseon Hwang, Dongyeop Lee, Seon Woo A An, Murat Artan, Keunhee Seo, Rachel Kaletsky, Rachel N Arey, Youngjae Ryu, Chang Man Ha, Yoon Ki Kim, Coleen T Murphy, Tae-Young Roh, Hong Gil Nam, Seung-Jae V Lee
Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C. elegans strains with mutations in daf-2/insulin/insulin-like growth factor 1 receptor. We find that daf-2 mutants display enhanced NMD activity and reduced levels of potentially aberrant transcripts...
March 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28271488/the-aminoacyl-trna-synthetase-complex
#12
Marc Mirande
Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. They are a family of twenty enzymes, one for each amino acid. By coupling an amino acid to a specific RNA triplet, the anticodon, they are responsible for interpretation of the genetic code. In addition to this translational, canonical role, several aminoacyl-tRNA synthetases also fulfill nontranslational, moonlighting functions. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28239189/pyrrolysyl-trna-synthetase-an-aminoacyl-trna-synthetase-for-genetic-code-expansion
#13
Ana Crnković, Tateki Suzuki, Dieter Söll, Noah M Reynolds
Genetic code expansion (GCE) has become a central topic of synthetic biology. GCE relies on engineered aminoacyl-tRNA synthetases (aaRSs) and a cognate tRNA species to allow codon reassignment by co-translational insertion of non-canonical amino acids (ncAAs) into proteins. Introduction of such amino acids increases the chemical diversity of recombinant proteins endowing them with novel properties. Such proteins serve in sophisticated biochemical and biophysical studies both in vitro and in vivo, they may become unique biomaterials or therapeutic agents, and they afford metabolic dependence of genetically modified organisms for biocontainment purposes...
June 2016: Croatica Chemica Acta. Arhiv za Kemiju
https://www.readbyqxmd.com/read/28237511/coupling-genetic-code-expansion-and-metabolic-engineering-for-synthetic-cells
#14
REVIEW
Jan-Stefan Völler, Nediljko Budisa
Orthogonal protein translation with noncanonical amino acids (ncAAs) has become a standard method in biosciences. Whereas much effort is made to broaden the chemical space of ncAAs, only few attempts on their systematic low-cost in situ production are reported until now. The main aim is to engineer cells with newly designed biosynthetic pathways coupled with orthogonal aminoacyl-tRNA synthetase/tRNA pairs (o-pairs). These should provide cost-effective solutions to industrially relevant bio-production problems, such as peptide/protein production beyond the canonical set of natural molecules and to expand the arsenal of chemistries available for living cells...
February 23, 2017: Current Opinion in Biotechnology
https://www.readbyqxmd.com/read/28236339/mutations-of-the-aminoacyl-trna-synthetases-sars-and-wars2-are-implicated-in-the-aetiology-of-autosomal-recessive-intellectual-disability
#15
Luciana Musante, Lucia Püttmann, Kimia Kahrizi, Masoud Garshasbi, Hao Hu, Henning Stehr, Bettina Lipkowitz, Sabine Otto, Lars R Jensen, Andreas Tzschach, Payman Jamali, Thomas Wienker, Hossein Najmabadi, Hans Hilger Ropers, Andreas W Kuss
Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNA(Ser) concentrations...
February 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/28235746/exploring-the-binding-sites-of-staphylococcus-aureus-phenylalanine-trna-synthetase-a-homology-model-approach
#16
Samar S Elbaramawi, Samy M Ibrahim, El-Sayed M Lashine, Mohamed E El-Sadek, Efi Mantzourani, Claire Simons
Increased resistance of MRSA (multidrug resistance Staphylococcus aureus) to anti-infective drugs is a threat to global health necessitating the development of anti-infectives with novel mechanisms of action. Phenylalanine tRNA synthetase (PheRS) is a unique enzyme of the aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes for protein biosynthesis. PheRS is an (αb)2 tetrameric enzyme composed of two alpha subunits (PheS) and two larger beta subunits (PheT). Our potential target in the drug development for the treatment of MRSA infections is the phenylalanine tRNA synthetase alpha subunit that contains the binding site for the natural substrate...
February 10, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28230768/bioinformatic-analysis-reveals-archaeal-trna-tyr-and-trna-trp-identities-in-bacteria
#17
Takahito Mukai, Noah M Reynolds, Ana Crnković, Dieter Söll
The tRNA identity elements for some amino acids are distinct between the bacterial and archaeal domains. Searching in recent genomic and metagenomic sequence data, we found some candidate phyla radiation (CPR) bacteria with archaeal tRNA identity for Tyr-tRNA and Trp-tRNA synthesis. These bacteria possess genes for tyrosyl-tRNA synthetase (TyrRS) and tryptophanyl-tRNA synthetase (TrpRS) predicted to be derived from DPANN superphylum archaea, while the cognate tRNA(Tyr) and tRNA(Trp) genes reveal bacterial or archaeal origins...
February 21, 2017: Life
https://www.readbyqxmd.com/read/28228619/a-case-of-anti-3-hydroxy-3-methylglutaryl-coenzyme-a-reductase-antibody-positive-paraneoplastic-necrotizing-myopathy-associated-with-advanced-gastric-cancer-that-responded-to-intravenous-immunoglobulin-therapy
#18
Tomohisa Yamaguchi, Akiko Matsunaga, Masamichi Ikawa, Norimichi Shirafuji, Ichizo Nishino, Tadanori Hamano
A 49-year-old woman presented with progressive muscle weakness of the limbs and dysphagia. Her past and family medical history were unremarkable and she did not take statins or any other medications. Laboratory tests showed that serum levels of creatine kinase were elevated (13,565 IU/l) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies were detected in the serum. Other autoantibodies to the nuclear (ANA), RNP, aminoacyl-tRNA synthetases (ARS), and signal recognition particle (SRP) were negative...
February 22, 2017: Rinshō Shinkeigaku, Clinical Neurology
https://www.readbyqxmd.com/read/28223419/papers-of-note-in-nature542-7641
#19
Annalisa M VanHook
This week's articles highlight a tRNA synthetase in mTORC1 signaling in fat cell metabolism and aging, the vulnerability of cancer cells to drugs that target proteostasis, and a mechanism by which stressed neurons expel protein aggregates and dysfunctional organelles.
February 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28220771/expanding-the-genetic-code-of-mus-musculus
#20
Songmi Han, Aerin Yang, Soonjang Lee, Han-Woong Lee, Chan Bae Park, Hee-Sung Park
Here we report the expansion of the genetic code of Mus musculus with various unnatural amino acids including N(ɛ)-acetyl-lysine. Stable integration of transgenes encoding an engineered N(ɛ)-acetyl-lysyl-tRNA synthetase (AcKRS)/tRNA(Pyl) pair into the mouse genome enables site-specific incorporation of unnatural amino acids into a target protein in response to the amber codon. We demonstrate temporal and spatial control of protein acetylation in various organs of the transgenic mouse using a recombinant green fluorescent protein (GFPuv) as a model protein...
February 21, 2017: Nature Communications
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