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tRNA Synthetase

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https://www.readbyqxmd.com/read/29138691/a-novel-dars2-mutation-in-a-japanese-patient-with-leukoencephalopathy-with-brainstem-and-spinal-cord-involvement-but-no-lactate-elevation
#1
Keiko Shimojima, Takafumi Higashiguchi, Kanako Kishimoto, Satoko Miyatake, Noriko Miyake, Jun-Ichi Takanashi, Naomichi Matsumoto, Toshiyuki Yamamoto
The mitochondrial aspartyl-tRNA synthetase 2 gene (DARS2) is responsible for leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). A Japanese patient with LBSL showed compound heterozygous DARS2 mutations c.358_359delinsTC (p.Gly120Ser) and c.228-15C>G (splicing error). This provides further evidence that most patients with LBSL show compound heterozygous mutations in DARS2 in association with a common splicing mutation in the splicing acceptor site of intron 2.
2017: Human Genome Variation
https://www.readbyqxmd.com/read/29137650/recessive-vars2-mutation-underlies-a-novel-syndrome-with-epilepsy-mental-retardation-short-stature-growth-hormone-deficiency-and-hypogonadism
#2
Abdulaziz Alsemari, Banan Al-Younes, Ewa Goljan, Dyala Jaroudi, Faisal BinHumaid, Brian F Meyer, Stefan T Arold, Dorota Monies
BACKGROUND: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency...
November 14, 2017: Human Genomics
https://www.readbyqxmd.com/read/29136176/mutations-in-metg-methionyl-trna-synthetase-and-trmd-trna-guanine-n1-methyltransferase-conferring-meropenem-tolerance-in-burkholderia-thailandensis
#3
Hyojeong Yi, Hyeri Lee, Kwang-Hwi Cho, Heenam Stanley Kim
Objectives: Although meropenem is widely used to treat Burkholderia infections, the response of Burkholderia pathogens to this antibiotic is largely unexplored. Methods: Burkholderia thailandensis, a model for Burkholderia spp., particularly Burkholderia mallei and Burkholderia pseudomallei, was challenged with a lethal level of meropenem and survivors were isolated. The genomes of two of the isolates were analysed to identify mutated genes and these genes were then specifically examined in more isolates to profile mutation diversity...
November 9, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29120675/utility-of-adenosine-monophosphate-detection-system-for-monitoring-the-activities-of-diverse-enzyme-reactions
#4
Subhanjan Mondal, Kevin Hsiao, Said A Goueli
Adenosine monophosphate (AMP) is a key cellular metabolite regulating energy homeostasis and signal transduction. AMP is also a product of various enzymatic reactions, many of which are dysregulated during disease conditions. Thus, monitoring the activities of these enzymes is a primary goal for developing modulators for these enzymes. In this study, we demonstrate the versatility of an enzyme-coupled assay that quantifies the amount of AMP produced by any enzymatic reaction regardless of its substrates. We successfully implemented it to enzyme reactions that use adenosine triphosphate (ATP) as a substrate (aminoacyl tRNA synthetase and DNA ligase) by an elaborate strategy of removing residual ATP and converting AMP produced into ATP; so it can be detected using luciferase/luciferin and generating light...
October 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/29120065/biallelic-mutations-in-mitochondrial-tryptophanyl-trna-synthetase-cause-levodopa-rresponsive-infantile-onset-parkinsonism
#5
E A Burke, S J Frucht, K Thompson, L A Wolfe, T Yokoyama, M Bertoni, Y Huang, M Sincan, D R Adams, R W Taylor, W A Gahl, C Toro, M C V Malicdan
Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause two different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy...
November 9, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/29117540/a-weak-spot-in-multiple-protozoan-parasites
#6
Wilson Wong
Eukaryotic protozoan parasites, including the etiological agents of malaria, toxoplasmosis, and leishmaniasis, collectively cause significant mortality in humans. In a recent issue of Structure,Jain et al. (2017) identify a set of quinazolinone-based derivatives targeting the parasitic prolyl-tRNA synthetase enzyme as promising drugs for the clearance of diverse parasites.
November 7, 2017: Structure
https://www.readbyqxmd.com/read/29111343/kinetic-origin-of-substrate-specificity-in-post-transfer-editing-by-leucyl-trna-synthetase
#7
Morana Dulic, Nevena Cvetesic, Igor Zivkovic, Andrés Palencia, Stephen Cusack, Branimir Bertosa, Ita Gruic-Sovulj
The intrinsic editing capacities of aminoacyl-tRNA synthetases ensure a high-fidelity translation of the amino acids that possess effective non-cognate aminoacylation surrogates. The dominant error-correction pathway comprises deacylation of misaminoacylated tRNA within the aminoacyl-tRNA synthetase editing site. To assess the origin of specificity of Escherichia coli leucyl-tRNA synthetase (LeuRS) against the cognate aminoacylation product in editing, we followed binding and catalysis independently using cognate leucyl- and non-cognate norvalyl-tRNA(Leu) and their non-hydrolyzable analogues...
October 27, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29107333/granzyme-b-disrupts-central-metabolism-and-protein-synthesis-in-bacteria-to-promote-an-immune-cell-death-program
#8
Farokh Dotiwala, Sumit Sen Santara, Andres Ariel Binker-Cosen, Bo Li, Sriram Chandrasekaran, Judy Lieberman
Human cytotoxic lymphocytes kill intracellular microbes. The cytotoxic granule granzyme proteases released by cytotoxic lymphocytes trigger oxidative bacterial death by disrupting electron transport, generating superoxide anion and inactivating bacterial oxidative defenses. However, they also cause non-oxidative cell death because anaerobic bacteria are also killed. Here, we use differential proteomics to identify granzyme B substrates in three unrelated bacteria: Escherichia coli, Listeria monocytogenes, and Mycobacteria tuberculosis...
October 25, 2017: Cell
https://www.readbyqxmd.com/read/29106828/expanding-the-scope-of-single-and-double-noncanonical-amino-acid-mutagenesis-in-mammalian-cells-using-orthogonal-polyspecific-leucyl-trna-synthetases
#9
Yunan Zheng, Raja Mukherjee, Melissa A Chin, Peter Igo, Martin J Gilgenast, Abhishek Chatterjee
Engineered aminoacyl-tRNA synthetase/tRNA pairs that enable site-specific incorporation of noncanonical amino acids (ncAAs) into proteins in living cells have emerged as powerful tools in chemical biology. The Escherichia coli-derived leucyl-tRNA synthetase (EcLeuRS)/tRNA pair is a promising candidate for ncAA mutagenesis in mammalian cells, but it has been engineered to charge only a limited set of ncAAs so far. Here we show that two highly polyspecific EcLeuRS mutants can efficiently charge a large array of useful ncAAs into proteins expressed in mammalian cells, while discriminating against the 20 canonical amino acids...
November 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/29106408/cell-type-specific-metabolic-labeling-of-nascent-proteomes-in-vivo
#10
Beatriz Alvarez-Castelao, Christoph T Schanzenbächer, Cyril Hanus, Caspar Glock, Susanne Tom Dieck, Aline R Dörrbaum, Ina Bartnik, Belquis Nassim-Assir, Elena Ciirdaeva, Anke Mueller, Daniela C Dieterich, David A Tirrell, Julian D Langer, Erin M Schuman
Although advances in protein labeling methods have made it possible to measure the proteome of mixed cell populations, it has not been possible to isolate cell-type-specific proteomes in vivo. This is because the existing methods for metabolic protein labeling in vivo access all cell types. We report the development of a transgenic mouse line where Cre-recombinase-induced expression of a mutant methionyl-tRNA synthetase (L274G) enables the cell-type-specific labeling of nascent proteins with a non-canonical amino-acid and click chemistry...
November 6, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/29096043/evolving-the-n-terminal-domain-of-pyrrolysyl-trna-synthetase-for-improved-incorporation-of-noncanonical-amino-acids
#11
Vangmayee Sharma, Yu Zeng, W Wesley Wang, Yuchen Qiao, Yadagiri Kurra, Wenshe Liu
By evolving the N-terminal domain of Methanosarcina mazei pyrrolysyl-tRNA synthetase (PylRS) that directly interacts with tRNAPyl, a mutant clone that displays improved amber suppression efficiency for the genetic incorporation of N-(tert-butoxycarbonyl)-l-lysine three-fold more than the wild type was identified. The identified mutations are R19H/H29R/T122S. Direct transfer of these mutations to two other PylRS mutants that were previously evolved for the genetic incorporation of N-acetyl- l-lysine and N-(4-azidobenzoxycarbonyl)- l-δ,ε-dehydrolysine respectively also improved the incorporation efficiency of these two noncanonical amino acids...
November 2, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29093389/the-onset-of-eosinophilic-pneumonia-preceding-anti-synthetase-syndrome
#12
Yoshimasa Hachisu, Yasuhiko Koga, Noriaki Sunaga, Chiharu Kashiwagi, Yuri Sawada, Yasuyuki Saito, Yusuke Tsukagoshi, Norimitsu Kasahara, Reiko Sakurai, Hiroaki Tsurumaki, Masakiyo Yatomi, Kyoichi Kaira, Akihiro Ono, Toshitaka Maeno, Takeshi Hisada
A 66-year-old man had been treated with prednisolone for eosinophilic pneumonia for 8 years. His slowly progressing cough and dyspnea were accompanied by elevated levels of fibrotic serological markers and an increased reticular shadow on chest computed tomography images. The patient had recently tested positive for anti-EJ antibodies, a type of anti-aminoacyl-tRNA synthetase antibody; therefore, we diagnosed him with an exacerbation of interstitial pneumonia due to anti-synthetase syndrome (ASS). He was treated with tacrolimus and an increased prednisolone dosage...
November 1, 2017: Internal Medicine
https://www.readbyqxmd.com/read/29092074/characterization-of-redundant-trnailes-with-cau-and-uau-anticodons-in-lactobacillus-plantarum
#13
Chie Tomikawa, Sylvie Auxilien, Vincent Guérineau, Yuya Yoshioka, Kiyo Miyoshi, Hiroyuki Hori, Dominique Fourmy, Kazuyuki Takai, Satoko Yoshizawa
In most eubacteria, the minor AUA isoleucine codon is decoded by tRNAIle2, which has a lysidine (L) in the anticodon loop. The lysidine is introduced by tRNAIle-lysidine synthetase (TilS) through post-transcriptional modification of cytidine to yield an LAU anticodon. Some bacteria, Lactobacillus plantarum for example, possess two tRNAIle2(UAU) genes in addition to, two tRNAIle2(CAU) genes and the tilS gene. tRNA expression from all these genes would generate redundancy in a tRNA that decodes a rare AUA codon...
October 30, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/29081953/defining-the-current-scope-and-limitations-of-dual-noncanonical-amino-acid-mutagenesis-in-mammalian-cells
#14
Yunan Zheng, Partha Sarathi Addy, Raja Mukherjee, Abhishek Chatterjee
The ability to site-specifically incorporate two distinct noncanonical amino acids (ncAAs) into the proteome of a mammalian cell with high fidelity and efficiency will have many enabling applications. It would require the use of two different engineered aminoacyl-tRNA synthetase (aaRS)/tRNA pairs, each suppressing a distinct nonsense codon, and which cross-react neither with each other, nor with their counterparts from the host cell. Three different aaRS/tRNA pairs have been developed so far to expand the genetic code of mammalian cells, which can be potentially combined in three unique ways to drive site-specific incorporation of two distinct ncAAs...
October 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/29079736/cysteinyl-trna-synthetase-governs-cysteine-polysulfidation-and-mitochondrial-bioenergetics
#15
Takaaki Akaike, Tomoaki Ida, Fan-Yan Wei, Motohiro Nishida, Yoshito Kumagai, Md Morshedul Alam, Hideshi Ihara, Tomohiro Sawa, Tetsuro Matsunaga, Shingo Kasamatsu, Akiyuki Nishimura, Masanobu Morita, Kazuhito Tomizawa, Akira Nishimura, Satoshi Watanabe, Kenji Inaba, Hiroshi Shima, Nobuhiro Tanuma, Minkyung Jung, Shigemoto Fujii, Yasuo Watanabe, Masaki Ohmuraya, Péter Nagy, Martin Feelisch, Jon M Fukuto, Hozumi Motohashi
Cysteine hydropersulfide (CysSSH) occurs in abundant quantities in various organisms, yet little is known about its biosynthesis and physiological functions. Extensive persulfide formation is apparent in cysteine-containing proteins in Escherichia coli and mammalian cells and is believed to result from post-translational processes involving hydrogen sulfide-related chemistry. Here we demonstrate effective CysSSH synthesis from the substrate L-cysteine, a reaction catalyzed by prokaryotic and mammalian cysteinyl-tRNA synthetases (CARSs)...
October 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29077934/interdependence-reflexivity-fidelity-impedance-matching-and-the-evolution-of-genetic-coding
#16
Charles W Carter, Peter R Wills
Genetic coding is generally thought to have required ribozymes whose functions were taken over by polypeptide aminoacyl-tRNA synthetases (aaRS). Two discoveries about aaRS and their interactions with tRNA substrates now furnish a unifying rationale for the opposite conclusion: that the key processes of the Central Dogma of molecular biology emerged simultaneously and naturally from simple origins in a peptide•RNA partnership, eliminating the epistemological utility of a prior RNA world. First, the two aaRS classes likely arose from opposite strands of the same ancestral gene, implying a simple genetic alphabet...
October 24, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29066549/selective-proteomic-analysis-of-antibiotic-tolerant-cellular-subpopulations-in-pseudomonas-aeruginosa-biofilms
#17
Brett M Babin, Lydia Atangcho, Mark B van Eldijk, Michael J Sweredoski, Annie Moradian, Sonja Hess, Tim Tolker-Nielsen, Dianne K Newman, David A Tirrell
Biofilm infections exhibit high tolerance against antibiotic treatment. The study of biofilms is complicated by phenotypic heterogeneity; biofilm subpopulations differ in their metabolic activities and their responses to antibiotics. Here, we describe the use of the bio-orthogonal noncanonical amino acid tagging (BONCAT) method to enable selective proteomic analysis of a Pseudomonas aeruginosa biofilm subpopulation. Through controlled expression of a mutant methionyl-tRNA synthetase, we targeted BONCAT labeling to cells in the regions of biofilm microcolonies that showed increased tolerance to antibiotics...
October 24, 2017: MBio
https://www.readbyqxmd.com/read/29065190/discovery-and-pharmacological-characterization-of-a-new-class-of-prolyl-trna-synthetase-inhibitor-for-anti-fibrosis-therapy
#18
Akira Shibata, Masako Kuno, Ryutaro Adachi, Yosuke Sato, Harumi Hattori, Atsushi Matsuda, Yuumi Okuzono, Keiko Igaki, Yusuke Tominari, Terufumi Takagi, Masato Yabuki, Masanori Okaniwa
Scleroderma has clinical characteristics including skin and other tissue fibrosis, but there is an unmet need for anti-fibrotic therapy. Halofuginone (HF) is a well-known anti-fibrosis agent in preclinical and clinical studies which exerts its effect via inhibition of TGF-β/Smad3 signaling pathway. Recently, prolyl-tRNA synthetase (PRS) was elucidated as a target protein for HF that binds to the proline binding site of the catalytic domain of PRS. Here, we characterized a new class of PRS inhibitor (T-3833261) that is carefully designed in a way that binds to the ATP site of the catalytic domain and does not disrupt binding of proline...
2017: PloS One
https://www.readbyqxmd.com/read/29045133/the-product-of-yersinia-pseudotuberculosis-mcc-operon-is-a-peptide-cytidine-antibiotic-activated-inside-producing-cells-by-the-tldd-e-protease
#19
Darya Tsibulskaya, Olga Mokina, Alexey Kulikovsky, Julia Piskunova, Konstantin Severinov, Marina Serebryakova, Svetlana Dubiley
Microcin C is a heptapeptide-adenylate antibiotic produced by some strains of Escherichia coli. Its peptide part is responsible for facilitated transport inside sensitive cells where it is proteolyzed with release of a toxic warhead-a nonhydrolyzable aspartamidyl-adenylate, which inhibits aspartyl-tRNA synthetase. Recently, a microcin C homologue from Bacillus amyloliquefaciens containing a longer peptide part modified with carboxymethyl-cytosine instead of adenosine was described, but no biological activity of this compound was revealed...
October 31, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29035363/crystal-structures-reveal-an-elusive-functional-domain-of-pyrrolysyl-trna-synthetase
#20
Tateki Suzuki, Corwin Miller, Li-Tao Guo, Joanne M L Ho, David I Bryson, Yane-Shih Wang, David R Liu, Dieter Söll
Pyrrolysyl-tRNA synthetase (PylRS) is a major tool in genetic code expansion using noncanonical amino acids, yet its structure and function are not completely understood. Here we describe the crystal structure of the previously uncharacterized essential N-terminal domain of this unique enzyme in complex with tRNA(Pyl). This structure explains why PylRS remains orthogonal in a broad range of organisms, from bacteria to humans. The structure also illustrates why tRNA(Pyl) recognition by PylRS is anticodon independent: the anticodon does not contact the enzyme...
October 16, 2017: Nature Chemical Biology
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