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tRNA Synthetase

Xiaokun Xu, Haibo Zhou, Yang Liu, Xiaotong Liu, Jun Fu, Aiying Li, Yue-Zhong Li, Yuemao Shen, Xiaoying Bian, Youming Zhang
The indole alkaloid antibiotic chuangxinmycin, from Actinobacteria Actinoplanes tsinanensis, containing a unique thiopyrano[4,3,2- cd]indole scaffold, is a potent and selective inhibitor of bacterial tryptophanyl-tRNA synthetase. The chuangxinmycin biosynthetic gene cluster was identified by in silico analysis of the genome sequence, then verified by heterologous expression. Systemic gene inactivation and intermediate identification determined the minimum set of genes for unique thiopyrano[4,3,2- cd]indole formation and the concerted action of a radical S-adenosylmethionine protein plus an unknown protein for addition of the 3-methyl group...
March 22, 2018: Journal of Natural Products
Fawzi Khoder-Agha, José M Dias, Martine Comisso, Marc Mirande
BACKGROUND: An important step in human immunodeficiency virus type 1 (HIV-1) replication is the packaging of tRNA3 Lys from the host cell, which plays the role of primer RNA in the process of initiation of reverse transcription. The viral GagPol polyprotein precursor, and the human mitochondrial lysyl-tRNA synthetase (mLysRS) from the host cell, have been proposed to be involved in the packaging process. More specifically, the catalytic domain of mLysRS is supposed to interact with the transframe (TF or p6*) and integrase (IN) domains of the Pol region of the GagPol polyprotein...
March 21, 2018: BMC Biochemistry
Dillon F Da Fonte, Chris J Martyniuk, Lei Xing, Vance L Trudeau
Radial glial cells (RGCs) are the main macroglia in the teleost brain and have established roles in neurogenesis and neurosteroidogenesis. They are the only brain cell type expressing aromatase B ( cyp19a1b ), the enzyme that synthesizes estrogens from androgen precursors. There are few studies on the regulation of RGC functions, but our previous investigations demonstrated that dopamine stimulates cyp19a1b expression in goldfish RGCs, while secretoneurin A (SNa) inhibits the expression of this enzyme. Here, we determine the range of proteins and cellular processes responsive to SNa treatments in these steroidogenic cells...
2018: Frontiers in Endocrinology
Mafalda Santos, Patricia M Pereira, A Sofia Varanda, Joana Carvalho, Mafalda Azevedo, Denisa D Mateus, Nuno Mendes, Patricia Oliveira, Fábio Trindade, Marta Teixeira Pinto, Renata Bordeira-Carriço, Fátima Carneiro, Rui Vitorino, Carla Oliveira, Manuel A S Santos
Deregulation of tRNAs, aminoacyl-tRNA synthetases and tRNA modifying enzymes are common in cancer, raising the hypothesis that protein synthesis efficiency and accuracy (mistranslation) are compromised in tumors. We show here that human colon tumors and xenograft tumors produced in mice by two epithelial cancer cell lines mistranslate 2- to 4-fold more frequently than normal tissue. To clarify if protein mistranslation plays a role in tumor biology, we expressed mutant Ser-tRNAs that misincorporate Ser-at-Ala (frequent error) and Ser-at-Leu (infrequent error) in NIH3T3 cells and investigated how they responded to the proteome instability generated by the amino acid misincorporations...
March 20, 2018: RNA Biology
Bryan Markinson, Mahmoud Ghannoum, Tate Winter, Anthony Rycerz, Fernando Rock, Aditya K Gupta
Onychomycosis is a fungal infection of the nail primarily caused by the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. The topical-based treatment of onychomycosis remains a challenge because of the difficulty associated with penetrating the dense, protective structure of the keratinized nail plate. Tavaborole is a novel small-molecule antifungal agent recently approved in the United States for the topical treatment of toenail onychomycosis. The low molecular weight, slight water solubility, and boron chemistry of tavaborole maximize nail penetration after topical application, allowing for effective targeting of the infection in the nail bed...
January 2018: Journal of the American Podiatric Medical Association
Youngzee Song, Huihao Zhou, My-Nuong Vo, Yi Shi, Mir Hussain Nawaz, Oscar Vargas-Rodriguez, Jolene K Diedrich, John R Yates, Shuji Kishi, Karin Musier-Forsyth, Paul Schimmel
In the original version of this Article, extraneous text not belonging to the article was accidentally appended to end of the first paragraph of the discussion. This error has now been corrected in both the PDF and HTML versions of the Article.
March 13, 2018: Nature Communications
Noriho Sakamoto, Hiroshi Ishimoto, Tomoyuki Kakugawa, Minoru Satoh, Tomoko Hasegawa, Shin Tanaka, Atsuko Hara, Shota Nakashima, Hirokazu Yura, Takuto Miyamura, Hanako Koyama, Towako Morita, Seiko Nakamichi, Yasushi Obase, Yuji Ishimatsu, Hiroshi Mukae
BACKGROUND: Interstitial lung disease (ILD) is a prognostic indicator of poor outcome in myositis. Although the pathogenesis of myositis-associated ILD is not well understood, neutrophils are thought to play a pivotal role. Neutrophils store azurophil granules that contain defensins, which are antimicrobial peptides that regulate the inflammatory response. Here, we evaluated levels of the human neutrophil peptides (HNPs) α-defensin 1 through 3 in patients with myositis-associated ILD to determine whether HNPs represent disease markers and play a role in the pathogenesis of myositis-associated ILD...
March 12, 2018: BMC Pulmonary Medicine
Peter Chung, Hope Northrup, Misbah Azmath, Ricardo A Mosquera, Shade Moody, Aravind Yadav
Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases...
2018: Case Reports in Pediatrics
Stuart J Grice, James N Sleigh, M Zameel Cader
Dominant mutations in GARS , encoding the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and Charcot-Marie-Tooth disease type 2D (CMT2D). This genetic disorder exemplifies a recurring paradigm in neurodegeneration, in which mutations in essential genes cause selective degeneration of the nervous system. Recent evidence suggests that the mechanism underlying CMT2D involves extracellular neomorphic binding of mutant GlyRS to neuronally-expressed proteins. Consistent with this, our previous studies indicate a non-cell autonomous mechanism, whereby mutant GlyRS is secreted and interacts with the neuromuscular junction (NMJ)...
2018: Frontiers in Molecular Neuroscience
Zhongying Mo, Xiaobei Zhao, Huaqing Liu, Qinghua Hu, Xu-Qiao Chen, Jessica Pham, Na Wei, Ze Liu, Jiadong Zhou, Robert W Burgess, Samuel L Pfaff, C Thomas Caskey, Chengbiao Wu, Ge Bai, Xiang-Lei Yang
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease's specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset...
March 8, 2018: Nature Communications
O S Nikonov, M S Nemchinova, V G Klyashtornii, E Yu Nikonova, M B Garber
The currently available structural information is insufficient for a detailed analysis of interactions between human glycyl-tRNA synthetase (GARS) and enterovirus IRESs. At the same time, this information is required in order to understand how this IRES trans-acting factor (ITAF) functions during viral mRNA translation, which is in turn crucial for the development of direct-action antiviral agents. In this paper, a theoretical model of the complex between a cadicivirus A IRES fragment and the anticodon-binding domain of human GARS is constructed using molecular dynamics simulation based on all of the available structural and biochemical data...
January 2018: Molekuliarnaia Biologiia
E Yu Nikonova, A O Mihaylina, M S Nemchinova, M B Garber, O S Nikonov
A full analysis has been conducted of the sequences and secondary structures of viral type-I or related IRESs identified in all of the elements that correspond to the previously described minimal fragment of the enterovirus C IRES, which mimics the glycine tRNA anticodon hairpin in the IRES structure and is necessary for the specific binding of glycyl-tRNA synthetase. Experiments on human glycyl-tRNA synthetase binding with the mRNA fragments of several taxonomically distant viruses showed that the binding constants of these complexes are similar...
January 2018: Molekuliarnaia Biologiia
Pallavi A Patil, Andrew M Blakely, Kara A Lombardo, Jason T Machan, Thomas J Miner, Li-Juan Wang, Alexander S Marwaha, Andres Matoso
INTRODUCTION: The tumor microenvironment is increasingly important in several tumors. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas. METHODS: Tissue microarrays were constructed from gastrectomy specimens, 2004-2013. Immunohistochemistry was performed for programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate-binding protein 5 (GBP5), tumor-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1, and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6...
February 28, 2018: Histopathology
Sanghati Roy Chowdhury, Udayaditya Sen
Vibrio cholerae, experiences a highly hostile environment at human intestine which trigger the induction of various heat shock genes. VcHsp15, the hslR gene product of V. cholerae O395 is a highly up regulated protein which targets erroneously dislodged 50S subunit upon heat shock that carries a tRNA attached to the abortive nascent polypeptide chain, and recycle it for another round of translation. In this study we report the crystal structure of VcHsp15 at 2.33 Å. Although the structure of VcHsp15 share very similar fold to E...
February 24, 2018: Biochemical and Biophysical Research Communications
Hidetoshi Teramoto, Yoshimi Amano, Fumie Iraha, Katsura Kojima, Takuhiro Ito, Kensaku Sakamoto
The genetic code in bacteria and animal cells has been expanded to incorporate novel amino acids into proteins. Recent efforts have enabled genetic code expansion in nematodes, flies, and mice, whereas such engineering is rare with industrially useful animals. In the present study, we engineered the silkworm Bombyx mori to synthesize silk fiber functionalized with azidophenylalanine. For this purpose, we developed a bacterial system to screen for B. mori phenylalanyl-tRNA synthetases with altered amino-acid specificity...
February 26, 2018: ACS Synthetic Biology
Sandra Pereira, Mariana Adrião, Mafalda Sampaio, Margarida Ayres Basto, Esmeralda Rodrigues, Laura Vilarinho, Elisa Leão Teles, Isabel Alonso, Miguel Leão
INTRODUCTION: Combined oxidative phosphorylation deficiency 20 (COXPD20) is a mitochondrial respiratory chain complex (RC) disorder, caused by disease-causing variants in the VARS2 gene, which encodes a mitochondrial aminoacyl-tRNA synthetase. Here we describe a patient with fatal mitochondrial encephalopathy caused by a homozygous VARS2 gene missense variant. CASE REPORT: We report the case of a girl, the first child of non-consanguineous and healthy parents, born from an uneventful term pregnancy, who presented, in the neonatal period, major hypotonia and microcephaly...
February 25, 2018: JIMD Reports
Baole Zhang, Steff De Graef, Manesh Nautiyal, Luping Pang, Bharat Gadakh, Matheus Froeyen, Lieve Van Mellaert, Sergei V Strelkov, Stephen D Weeks, Arthur Van Aerschot
Aminoacyl-tRNA synthetases (aaRSs) are enzymes that precisely attach an amino acid to its cognate tRNA. This process, which is essential for protein translation, is considered a viable target for the development of novel antimicrobial agents, provided species selective inhibitors can be identified. Aminoacyl-sulfamoyl adenosines (aaSAs) are potent orthologue specific aaRS inhibitors that demonstrate nanomolar affinities in vitro but have limited uptake. Following up on our previous work on substitution of the base moiety, we evaluated the effect of the N3 -position of the adenine by synthesizing the corresponding 3-deazaadenosine analogues (aaS3DAs)...
February 14, 2018: European Journal of Medicinal Chemistry
Tom Froese, Jorge I Campos, Kosuke Fujishima, Daisuke Kiga, Nathaniel Virgo
Theories of the origin of the genetic code typically appeal to natural selection and/or mutation of hereditable traits to explain its regularities and error robustness, yet the present translation system presupposes high-fidelity replication. Woese's solution to this bootstrapping problem was to assume that code optimization had played a key role in reducing the effect of errors caused by the early translation system. He further conjectured that initially evolution was dominated by horizontal exchange of cellular components among loosely organized protocells ("progenotes"), rather than by vertical transmission of genes...
February 23, 2018: Scientific Reports
Greana Kirubakar, Jayaseelan Murugaiyan, Christoph Schaudinn, Flavia Dematheis, Gudrun Holland, Murat Eravci, Christoph Weise, Uwe Roesler, Astrid Lewin
Lysyl-phosphatidylglycerol (L-PG) is one of the components of the mycobacterial membrane which contributes to the resistance towards cationic antimicrobial peptides, a host-induced frontline defense against invading pathogens. Its production is catalyzed by LysX, a bifunctional protein with lysyl transferase and lysyl-tRNA synthetase activity. Comparative proteome analysis of a lysX mutant of M. avium strain104 and the wild type indicated that the lysX mutant strain undergoes a transition in phenotype by switching the carbon metabolism to β-oxidation of fatty acids along with accumulation of lipid inclusions...
February 19, 2018: Journal of Infectious Diseases
Yoshio Kimura, Chihiro Tanaka, Manami Oka
Myxococcus xanthus generates diadenosine tetraphosphates (Ap4 A) and diadenosine pentaphosphates (Ap5 A) under various stress conditions. M. xanthus lysyl-tRNA synthetase (LysS) efficiently synthesizes Ap4 A from ATP, Ap5 A from ATP and adenosine tetraphosphate (Ap4 ), and Ap4 from ATP and triphosphate. To identify other M. xanthus enzymes that can catalyze Ap4 A and Ap4 synthesis, 15 M. xanthus aminoacyl-tRNA synthetases (aaRSs), four acyl-CoA synthetases (Acys), three acetyl-CoA synthetases (Aces), phosphoglycerate kinase (Pgk), and adenylate kinase (Adk) were expressed in Escherichia coli and examined for Ap4 A or Ap4 synthetase activity using ATP or ATP and triphosphate as substrates...
February 21, 2018: Current Microbiology
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