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tRNA Synthetase

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https://www.readbyqxmd.com/read/28534666/human-aminoacyl-trna-synthetases-in-diseases-of-the-nervous-system
#1
Jana Ognjenović, Miljan Simonović
Aminoacyl-tRNA synthetases (AaRSs) are ubiquitously expressed enzymes that ensure accurate translation of the genetic information into functional proteins. These enzymes also execute a variety of non-canonical functions that are significant for regulation of diverse cellular processes and that reside outside the realm of protein synthesis. Associations between faults in AaRS-mediated processes and human diseases have been long recognized. Most recent research findings strongly argue that 10 cytosolic and 14 mitochondrial AaRSs are implicated in some form of pathology of the human nervous system...
May 23, 2017: RNA Biology
https://www.readbyqxmd.com/read/28531329/alternative-stable-conformation-capable-of-protein-misinteraction-links-trna-synthetase-to-peripheral-neuropathy
#2
David Blocquel, Sheng Li, Na Wei, Herwin Daub, Mathew Sajish, Maria-Luise Erfurth, Grace Kooi, Jiadong Zhou, Ge Bai, Paul Schimmel, Albena Jordanova, Xiang-Lei Yang
While having multiple aminoacyl-tRNA synthetases implicated in Charcot-Marie-Tooth (CMT) disease suggests a common mechanism, a defect in enzymatic activity is not shared among the CMT-causing mutants. Protein misfolding is a common hypothesis underlying the development of many neurological diseases. Its process usually involves an initial reduction in protein stability and then the subsequent oligomerization and aggregation. Here, we study the structural effect of three CMT-causing mutations in tyrosyl-tRNA synthetase (TyrRS or YARS)...
May 22, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28516732/diadenosine-tetraphosphate-ap4a-an-e-coli-alarmone-or-a-damage-metabolite
#3
Dragana Despotović, Alexander Brandis, Alon Savidor, Yishai Levin, Laura Fumagalli, Dan S Tawfik
Under stress, metabolism is changing: specific up- or down-regulation of proteins and metabolites occurs as well as side-effects. Distinguishing specific stress-signaling metabolites (alarmones) from side-products (damage metabolites) is not trivial. One example is diadenosine tetraphosphate, Ap4A - a side-product of aminoacyl-tRNA synthetases found in all domains of life. The earliest observations suggested that Ap4A serves as an alarmone for heat stress in E. coli. However, despite 50 years of research, the signaling mechanisms associated with Ap4A remain unknown...
May 18, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28501621/discovery-of-a-novel-prolyl-trna-synthetase-inhibitor-and-elucidation-of-its-binding-mode-to-the-atp-site-in-complex-with-l-proline
#4
Ryutaro Adachi, Kengo Okada, Robert Skene, Kazumasa Ogawa, Masanori Miwa, Kazuhiro Tsuchinaga, Shoichi Ohkubo, Tsutomu Henta, Tomohiro Kawamoto
Prolyl-tRNA synthetase (PRS) is a member of the aminoacyl-tRNA synthetase family of enzymes and catalyzes the synthesis of prolyl-tRNA(Pro) using ATP, l-proline, and tRNA(Pro) as substrates. An ATP-dependent PRS inhibitor, halofuginone, was shown to suppress autoimmune responses, suggesting that the inhibition of PRS is a potential therapeutic approach for inflammatory diseases. Although a few PRS inhibitors have been derivatized from natural sources or substrate mimetics, small-molecule human PRS inhibitors have not been reported...
May 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28500387/thermal-adaptation-strategies-of-the-extremophile-bacterium-thermus-filiformis-based-on-multi-omics-analysis
#5
F Mandelli, M B Couger, D A A Paixão, C B Machado, C M Carnielli, J A Aricetti, I Polikarpov, R Prade, C Caldana, A F Paes Leme, A Z Mercadante, D M Riaño-Pachón, Fabio Marcio Squina
Thermus filiformis is an aerobic thermophilic bacterium isolated from a hot spring in New Zealand. The experimental study of the mechanisms of thermal adaptation is important to unveil response strategies of the microorganism to stress. In this study, the main pathways involved on T. filiformis thermoadaptation, as well as, thermozymes with potential biotechnological applications were revealed based on omics approaches. The strategy adopted in this study disclosed that pathways related to the carbohydrate metabolism were affected in response to thermoadaptation...
May 12, 2017: Extremophiles: Life Under Extreme Conditions
https://www.readbyqxmd.com/read/28493438/deficient-activity-of-alanyl-trna-synthetase-underlies-an-autosomal-recessive-syndrome-of-progressive-microcephaly-hypomyelination-and-epileptic-encephalopathy
#6
Tojo Nakayama, Jiang Wu, Patricia Galvin-Parton, Jody Weiss, Mary R Andriola, R Sean Hill, Dylan Vaughan, Malak El-Quessny, Brenda J Barry, Jennifer N Partlow, A James Barkovich, Jiqiang Ling, Ganeshwaran H Mochida
Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth (CMT) disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy and spasticity...
May 11, 2017: Human Mutation
https://www.readbyqxmd.com/read/28487430/rna-dependent-cysteine-biosynthesis-in-bacteria-and-archaea
#7
Takahito Mukai, Ana Crnković, Takuya Umehara, Natalia N Ivanova, Nikos C Kyrpides, Dieter Söll
The diversity of the genetic code systems used by microbes on earth is yet to be elucidated. It is known that certain methanogenic archaea employ an alternative system for cysteine (Cys) biosynthesis and encoding; tRNA(Cys) is first acylated with phosphoserine (Sep) by O-phosphoseryl-tRNA synthetase (SepRS) and then converted to Cys-tRNA(Cys) by Sep-tRNA:Cys-tRNA synthase (SepCysS). In this study, we searched all genomic and metagenomic protein sequence data in the Integrated Microbial Genomes (IMG) system and at the NCBI to reveal new clades of SepRS and SepCysS proteins belonging to diverse archaea in the four major groups (DPANN, Euryarchaeota, TACK, and Asgard) and two groups of bacteria ("Candidatus Parcubacteria" and Chloroflexi)...
May 9, 2017: MBio
https://www.readbyqxmd.com/read/28487390/activation-of-the-amino-acid-response-pathway-blunts-the-effects-of-cardiac-stress
#8
Pu Qin, Pelin Arabacilar, Roberta E Bernard, Weike Bao, Alan R Olzinski, Yuanjun Guo, Hind Lal, Stephen H Eisennagel, Michael C Platchek, Wensheng Xie, Julius Del Rosario, Mohamad Nayal, Quinn Lu, Theresa Roethke, Christine G Schnackenberg, Fe Wright, Michael P Quaile, Wendy S Halsey, Ashley M Hughes, Ganesh M Sathe, George P Livi, Robert B Kirkpatrick, Xiaoyan A Qu, Deepak K Rajpal, Maria Faelth Savitski, Marcus Bantscheff, Gerard Joberty, Giovanna Bergamini, Thomas L Force, Gregory J Gatto, Erding Hu, Robert N Willette
BACKGROUND: The amino acid response (AAR) is an evolutionarily conserved protective mechanism activated by amino acid deficiency through a key kinase, general control nonderepressible 2. In addition to mobilizing amino acids, the AAR broadly affects gene and protein expression in a variety of pathways and elicits antifibrotic, autophagic, and anti-inflammatory activities. However, little is known regarding its role in cardiac stress. Our aim was to investigate the effects of halofuginone, a prolyl-tRNA synthetase inhibitor, on the AAR pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure...
May 9, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28484050/using-tn-seq-to-identify-pigmentation-related-genes-of-porphyromonas-gingivalis-characterization-of-the-role-of-a-putative-glycosyltransferase
#9
Brian A Klein, Louis P Cornacchione, Marisha Collins, Michael H Malamy, Margaret J Duncan, Linden T Hu
Cellular pigmentation is an important virulence factor of the oral pathogen Porphyromonas gingivalis Pigmentation has been associated with many bacterial functions including but not limited to: colonization, maintaining a local anaerobic environment by binding oxygen molecules, and defense against reactive oxygen species (ROS) produced by immune cells. Pigmentation-associated loci identified to date have involved lipopolysaccharide, fimbriae and haem acquisition and processing. We utilized a transposon mutant library of P...
May 8, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28482005/the-rapid-evolution-of-an-ohnolog-contributes-to-the-ecological-specialization-of-incipient-yeast-species
#10
Chris Eberlein, Lou Nielly-Thibault, Halim Maaroufi, Alexandre K Dubé, Jean-Baptiste Leducq, Guillaume Charron, Christian R Landry
Identifying the molecular changes that lead to ecological specialization during speciation is one of the major goals of molecular evolution. One question that remains to be thoroughly investigated is whether ecological specialization derives strictly from adaptive changes and their associated trade-offs, or from conditionally neutral mutations that accumulate under relaxed selection. We used whole-genome sequencing, genome annotation and computational analyses to identify genes that have rapidly diverged between two incipient species of Saccharomyces paradoxus that occupy different climatic regions along a south-west to north-east gradient...
May 8, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/28479744/high-throughput-virtual-screening-to-identify-novel-natural-product-inhibitors-for-methionyltrna-synthetase-of-brucella-melitensis
#11
Madhulata Kumari, Subhash Chandra, Neeraj Tiwari, Naidu Subbarao
The Brucella melitensis methionyl-tRNA-synthetase (MetRSBm) is a promising target for brucellosis drug development. The virtual screening of large libraries of a drug like molecules against a protein target is a common strategy used to identify novel inhibitors. A High throughput virtual screening was performed to identify hits to the potential antibrucellosis drug target, MetRSBm. The best inhibitor identified from the literature survey was 1312, 1415, and 1430. In the virtual screening 56,400 compounds of ChEMBL antimycobacterial library, 1596 approved drugs, 419 Natural product IV library, and 2396 methionine analogous were docked and rescoring, identified top 10 ranked compounds as anti-mycobacterial leads showing G-scores -10...
2017: Bioinformation
https://www.readbyqxmd.com/read/28469666/anatomical-distributional-defects-in-mutant-genes-associated-with-dominant-intermediate-charcot-marie-tooth-disease-type-c-in-an-adenovirus-mediated-mouse-model
#12
SeoJin Lee, Sandesh Panthi, Hyun Woo Jo, Jaeyoung Cho, Min-Sik Kim, Na Young Jeong, In Ok Song, Junyang Jung, Youngbuhm Huh
Dominant intermediate Charcot-Marie-Tooth disease type C (DI-CMTC) is a dominantly inherited neuropathy that has been classified primarily based on motor conduction velocity tests but is now known to involve axonal and demyelination features. DI-CMTC is linked to tyrosyl-tRNA synthetase (YARS)-associated neuropathies, which are caused by E196K and G41R missense mutations and a single de novo deletion (153-156delVKQV). It is well-established that these YARS mutations induce neuronal dysfunction, morphological symptoms involving axonal degeneration, and impaired motor performance...
March 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28465105/optimization-of-a-binding-fragment-targeting-the-enlarged-methionine-pocket-leads-to-potent-trypanosoma-brucei-methionyl-trna-synthetase-inhibitors
#13
Wenlin Huang, Zhongsheng Zhang, Ranae M Ranade, J Robert Gillespie, Ximena Barros-Álvarez, Sharon A Creason, Sayaka Shibata, Christophe L M J Verlinde, Wim G J Hol, Frederick S Buckner, Erkang Fan
Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the "enlarged methionine pocket" (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4nM...
April 17, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28461832/new-insights-into-antisynthetase-syndrome
#14
Cojocaru Manole, Cojocaru Inimioara Mihaela, Chicos Bogdan
Antisynthetase syndrome (ASS) is a rare chronic autoimmune disorder (2-3 times more common in women than in men), associated with interstitial lung disease (the most important feature), dermatomyositis (DM), and polymyositis (PM). The cause of ASS is unknown. Recent developments in immunology have improved our knowledge and it is now possible to classify ASS according to the presence of myositis specific autoantibodies. The hallmark of ASS is the presence of serum autoantibodies directed against aminoacyl-tRNA synthetases (anti-ARS involved in protein synthesis)...
June 2016: Mædica
https://www.readbyqxmd.com/read/28461123/the-long-term-outcome-of-interstitial-lung-disease-with-anti-aminoacyl-trna-synthetase-antibodies
#15
Kiminobu Tanizawa, Tomohiro Handa, Ran Nakashima, Takeshi Kubo, Yuji Hosono, Kizuku Watanabe, Kensaku Aihara, Kohei Ikezoe, Akihiko Sokai, Yoshinari Nakatsuka, Yoshio Taguchi, Kazuhiro Hatta, Satoshi Noma, Yoichiro Kobashi, Akihiko Yoshizawa, Toru Oga, Toyohiro Hirai, Kazuo Chin, Sonoko Nagai, Takateru Izumi, Tsuneyo Mimori, Michiaki Mishima
RATIONALE: Anti-aminoacyl transfer RNA synthetase antibodies (anti-ARS) are a group of myositis-specific autoantibodies that are detected in the sera of patients with polymyositis and dermatomyositis (PM/DM) and also in those of patients with idiopathic interstitial pneumonias without any connective tissue disease (CTD), including PM/DM. Although we reported the clinical characteristics of interstitial lung disease with anti-ARS antibodies (ARS-ILD) with and without PM/DM, the long-term prognosis of ARS-ILD remains undetermined...
April 15, 2017: Respiratory Medicine
https://www.readbyqxmd.com/read/28455447/acetylation-of-lysine-%C3%AF%C2%B5-amino-groups-regulates-aminoacyl-trna-synthetase-activity-in-escherichia-coli
#16
Qing Ye, Quan-Quan Ji, Wei Yan, Fang Yang, En-Duo Wang
Previous proteomic analyses have shown that aminoacyl-tRNA synthetases (aaRSs) in many organisms can be modified by acetylation of lysine (Lys). In this present study, leucyl-tRNA synthetase and arginyl-tRNA synthetase from Escherichia coli (EcLeuRS and EcArgRS) were overexpressed and purified, and found to be acetylated on Lys residues by mass spectrometry (MS). Glutamine (Gln) scanning mutagenesis revealed that Lys619, Lys624 and Lys809 in EcLeuRS and Lys126 and Lys408 in EcArgRS might play important roles in enzyme activity...
April 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28451794/comparison-of-long-term-prognosis-and-relapse-of-dermatomyositis-complicated-with-interstitial-pneumonia-according-to-autoantibodies-anti-aminoacyl-trna-synthetase-antibodies-versus-anti-melanoma-differentiation-associated-gene-5-antibody
#17
Kentaro Isoda, Takuya Kotani, Tohru Takeuchi, Takao Kiboshi, Kenichiro Hata, Takaaki Ishida, Kenichiro Otani, Takao Kamimori, Hiroshi Fujiwara, Takeshi Shoda, Shigeki Makino
The aim of this study was to investigate long-term prognosis and relapse of dermatomyositis complicated with interstitial pneumonia (DMIP) according to anti-aminoacyl tRNA synthetase (ARS) antibodies and anti-melanoma differentiation-associated gene 5 (MDA5) antibody. This retrospective study comprised 36 patients with DMIP who were divided into the anti-ARS antibody-positive group (ARS+) (n = 12), anti MDA5 antibody-positive group (MDA5+) (n = 11), double-negative group (ARS-/MDA5-) (n = 11), and double-positive group (ARS+/MDA5+) (n = 1)...
April 27, 2017: Rheumatology International
https://www.readbyqxmd.com/read/28451254/fluorogenic-protein-labeling-using-a-genetically-encoded-unstrained-alkene
#18
X Shang, X Song, C Faller, R Lai, H Li, R Cerny, W Niu, J Guo
We developed a new fluorogenic bioorthogonal reaction that is based on the inverse electron-demand Diels-Alder reaction between styrene (an unstrained alkene) and a simple tetrazine. The reaction forms a new fluorophore with no literature precedent. We have identified an aminoacyl-tRNA synthetase/tRNA pair for the efficient and site-specific incorporation of a styrene-containing amino acid into proteins in response to amber nonsense codon. Fluorogenic labeling of purified proteins and intact proteins in live cells were demonstrated...
February 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28439027/biochemical-and-structural-characterization-of-oxygen-sensitive-2-thiouridine-synthesis-catalyzed-by-an-iron-sulfur-protein-ttua
#19
Minghao Chen, Shin-Ichi Asai, Shun Narai, Shusuke Nambu, Naoki Omura, Yuriko Sakaguchi, Tsutomu Suzuki, Masao Ikeda-Saito, Kimitsuna Watanabe, Min Yao, Naoki Shigi, Yoshikazu Tanaka
Two-thiouridine (s(2)U) at position 54 of transfer RNA (tRNA) is a posttranscriptional modification that enables thermophilic bacteria to survive in high-temperature environments. s(2)U is produced by the combined action of two proteins, 2-thiouridine synthetase TtuA and 2-thiouridine synthesis sulfur carrier protein TtuB, which act as a sulfur (S) transfer enzyme and a ubiquitin-like S donor, respectively. Despite the accumulation of biochemical data in vivo, the enzymatic activity by TtuA/TtuB has rarely been observed in vitro, which has hindered examination of the molecular mechanism of S transfer...
May 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28427904/leishmania-donovani-tyrosyl-trna-synthetase-structure-in-complex-with-a-tyrosyl-adenylate-analog-and-comparisons-with-human-and-protozoan-counterparts
#20
Ximena Barros-Álvarez, Keshia M Kerchner, Cho Yeow Koh, Stewart Turley, Els Pardon, Jan Steyaert, Ranae M Ranade, J Robert Gillespie, Zhongsheng Zhang, Christophe L M J Verlinde, Erkang Fan, Frederick S Buckner, Wim G J Hol
The crystal structure of Leishmania donovani tyrosyl-tRNA synthetase (LdTyrRS) in complex with a nanobody and the tyrosyl adenylate analog TyrSA was determined at 2.75 Å resolution. Nanobodies are the variable domains of camelid heavy chain-only antibodies. The nanobody makes numerous crystal contacts and in addition reduces the flexibility of a loop of LdTyrRS. TyrSA is engaged in many interactions with active site residues occupying the tyrosine and adenine binding pockets. The LdTyrRS polypeptide chain consists of two pseudo-monomers, each consisting of two domains...
April 17, 2017: Biochimie
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