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Julian A Rycroft, Bridget Gollan, Grzegorz J Grabe, Alexander Hall, Angela M Cheverton, Gerald Larrouy-Maumus, Stephen A Hare, Sophie Helaine
Non-typhoidal Salmonella strains are responsible for invasive infections associated with high mortality and recurrence in sub-Saharan Africa, and there is strong evidence for clonal relapse following antibiotic treatment. Persisters are non-growing bacteria that are thought to be responsible for the recalcitrance of many infections to antibiotics. Toxin-antitoxin systems are stress-responsive elements that are important for Salmonella persister formation, specifically during infection. Here, we report the analysis of persister formation of clinical invasive strains of Salmonella Typhimurium and Enteritidis in human primary macrophages...
May 18, 2018: Nature Communications
Jie Cao, Qian-Qian Jin, Gui-Ming Wang, Hong-Lin Dong, Yong-Ming Feng, Jun-Sheng Tian, Ke-Ming Yun, Ying-Yuan Wang, Jun-Hong Sun
Deep vein thrombosis (DVT) and pulmonary embolism (PE) have high morbidity, reduce quality of life, and can cause death. Biomarkers or genetic risk factors have not been identified in patients with DVT. In present study, serum of 61 patients suffering from DVT and a rat DVT model (n = 10) were assayed by a proton nuclear magnetic resonance (1 H NMR) metabolomics technique combing with multivariate statistical analysis to identify the metabolites. The MetPA platform was used to identify differences in the metabolic pathways between the rat model and patients...
May 18, 2018: Scientific Reports
Tamara L Hendrickson
The introduction of manmade chemicals, including the herbicide atrazine, into the environment has led to the emergence of microorganisms with new biodegradation pathways. Esquirol et al. demonstrate that the AtzE enzyme catalyzes a central step in atrazine degradation and that expression of AtzE requires coexpression of the small protein AtzG. Remarkably, AtzG and AtzE appear to have evolved from GatC and GatA, components of an ancient enzyme involved in indirect tRNA aminoacylation, providing an elegant demonstration of metabolic repurposing...
May 18, 2018: Journal of Biological Chemistry
Martine Comisso, Alice Hadchouel, Jacques de Blic, Marc Mirande
Biallelic missense mutations in MARS are responsible for rare but severe cases of pulmonary alveolar proteinosis (PAP) prevalent on the island of La Réunion. MARS encodes cytosolic methionyl-tRNA synthetase (MetRS), an essential translation factor. The multisystemic effects observed in patients with this form of PAP is consistent with a loss-of-function defect in an ubiquitously expressed enzyme. The pathophysiological mechanisms involved in MARS related PAP are currently unknown. In this work, we analyzed the effect of the PAP related mutations in MARS on the thermal stability and on the catalytic parameters of the MetRS mutants, relative to wild-type...
May 18, 2018: FEBS Journal
Andrew C Yang, Haley du Bois, Niclas Olsson, David Gate, Benoit Lehallier, Daniela Berdnik, Kyle D Brewer, Carolyn R Bertozzi, Joshua E Elias, Tony Wyss-Coray
Bio-orthogonal tools enable cell-type-specific proteomics, a prerequisite to understanding biological processes in multicellular organisms. Here we report two engineered aminoacyl-tRNA synthetases for mammalian bio-orthogonal labeling: a tyrosyl ( ScTyrY34G ) and a phenylalanyl ( MmPheT412G ) tRNA synthetase that incorporate azide-bearing noncanonical amino acids specifically into the nascent proteomes of host cells. Azide-labeled proteins are chemoselectively tagged via azide-alkyne cycloadditions with fluorophores for imaging or affinity resins for mass spectrometric characterization...
May 18, 2018: Journal of the American Chemical Society
My-Nuong Vo, Markus Terrey, Jeong Woong Lee, Bappaditya Roy, James J Moresco, Litao Sun, Hongjun Fu, Qi Liu, Thomas G Weber, John R Yates, Kurt Fredrick, Paul Schimmel, Susan L Ackerman
Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aars sti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, we identified Ankrd16, a gene that acts epistatically with the Aars sti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS...
May 16, 2018: Nature
Hideaki Yamakawa, Eri Hagiwara, Hideya Kitamura, Tae Iwasawa, Ryota Otoshi, Naoto Aiko, Takuma Katano, Ryota Shintani, Satoshi Ikeda, Ryo Okuda, Akimasa Sekine, Tomohisa Baba, Shinichiro Iso, Kazuyoshi Kuwano, Shinji Sato, Takashi Ogura
BACKGROUND: Little has been reported on long-term pulmonary function trends among patients with interstitial lung disease associated with anti-aminoacyl-tRNA synthetase antibodies (ARS-ILD). OBJECTIVES: To clarify the factors predictive of progression in ARS-ILD based on patients' initial clinical and radiological features. METHODS: The clinical courses of 88 patients with > 1 year of follow-up data on pulmonary function tests (PFTs) were retrospectively analyzed...
May 16, 2018: Respiration; International Review of Thoracic Diseases
Krishna C Suddala, Javier Cabello-Villegas, Malgorzata Michnicka, Collin Marshall, Edward P Nikonowicz, Nils G Walter
In Gram-positive bacteria, T-box riboswitches control gene expression to maintain the cellular pools of aminoacylated tRNAs essential for protein biosynthesis. Co-transcriptional binding of an uncharged tRNA to the riboswitch stabilizes an antiterminator, allowing transcription read-through, whereas an aminoacylated tRNA does not. Recent structural studies have resolved two contact points between tRNA and Stem-I in the 5' half of the T-box riboswitch, but little is known about the mechanism empowering transcriptional control by a small, distal aminoacyl modification...
May 14, 2018: Nature Communications
Salman Shahid, Ashish Kabra, Surbhi Mundra, Ravi Kant Pal, Sarita Tripathi, Anupam Jain, Ashish Arora
BACKGROUND: Bacterial peptidyl-tRNA hydrolase (Pth) is an essential enzyme that alleviates tRNA starvation by recycling prematurely dissociated peptidyl-tRNAs. The specificity of Pth for N-blocked-aminoacyl-tRNA has been proposed to be contingent upon conserved residue N14 forming a hydrogen bond with the carbonyl of the first peptide bond in the substrate. M71 is involved in forming a conserved hydrogen bond with N14. Other interactions facilitating this recognition are not known. METHODS: The structure, dynamics, and stability of the M71A mutant of Pth from Vibrio cholerae (VcPth) were characterized by X-ray crystallography, NMR spectroscopy, MD simulations and DSC...
May 4, 2018: Biochimica et Biophysica Acta
Marcus Fislage, Jingji Zhang, Zuben Patrick Brown, Chandra Sekhar Mandava, Suparna Sanyal, Måns Ehrenberg, Joachim Frank
The GTPase EF-Tu in ternary complex with GTP and aminoacyl-tRNA (aa-tRNA) promotes rapid and accurate delivery of cognate aa-tRNAs to the ribosomal A site. Here we used cryo-EM to study the molecular origins of the accuracy of ribosome-aided recognition of a cognate ternary complex and the accuracy-amplifying role of the monitoring bases A1492, A1493 and G530 of the 16S rRNA. We used the GTPase-deficient EF-Tu variant H84A with native GTP, rather than non-cleavable GTP analogues, to trap a near-cognate ternary complex in high-resolution ribosomal complexes of varying codon-recognition accuracy...
May 4, 2018: Nucleic Acids Research
Emmanuelle Schmitt, Gabrielle Bourgeois, Muriel Gondry, Alexey Aleksandrov
Cyclodipeptide synthases (CDPSs) form various cyclodipeptides from two aminoacyl tRNAs via a stepwise mechanism with the formation of a dipeptidyl enzyme intermediate. As a final step of the catalytic reaction, the dipeptidyl group undergoes intramolecular cyclization to generate the target cyclodipeptide product. In this work, we investigated the cyclization reaction in the cyclodipeptide synthase AlbC using QM/MM methods and free energy simulations. The results indicate that the catalytic Y202 residue is in its neutral protonated form, and thus, is not likely to serve as a general base during the reaction...
May 4, 2018: Scientific Reports
Daewoo Pak, Yunsoo Kim, Zachary F Burton
The genetic code sectored via tRNA charging errors, and the code progressed toward closure and universality because of evolution of aminoacyl-tRNA synthetase (aaRS) and ribosome fidelity mechanisms. Class I and class II aaRS folds are identified as homologs. Five mechanisms toward code closure are highlighted: 1) aaRS proofreading to remove mischarged amino acids from tRNA; 2) accurate aaRS active site specification of amino acid substrates; 3) aaRS-tRNA anticodon recognition; 4) EF-TU and GTP hydrolysis proofreading of the tRNA-mRNA interaction; and 5) modification of tRNA wobble adenine to inosine...
May 4, 2018: Transcription
Christopher Francklyn, Herve Roy, Rebecca Alexander
The 11th IUBMB Focused Meeting on Aminoacyl-tRNA Synthetases was held in Clearwater Beach, Florida from 29 October⁻2 November 2017, with the aim of presenting the latest research on these enzymes and promoting interchange among aminoacyl-tRNA synthetase (ARS) researchers. Topics covered in the meeting included many areas of investigation, including ARS evolution, mechanism, editing functions, biology in prokaryotic and eukaryotic cells and their organelles, their roles in human diseases, and their application to problems in emerging areas of synthetic biology...
May 1, 2018: Biomolecules
Shruti Chakraborty, Sayak Ganguli, Aritra Chowdhury, Michael Ibba, Rajat Banerjee
BACKGROUND: Under oxidative stress cytoplasmic aminoacyl-tRNA synthetase (aaRSs) substrate specificity can be compromised, leading to tRNA mischarging and mistranslation of the proteome. Whether similar processes occur in mitochondria, which are major cellular sources of reactive oxygen species (ROS), is unknown. However, relaxed substrate specificity in yeast mitochondrial phenylalanyl-tRNA synthetase (ScmitPheRS) has been reported to increase tRNA mischarging and blocks mitochondrial biogenesis...
April 30, 2018: Biochimica et Biophysica Acta
Xiujuan Yang, Gang Li, Yuesheng Tian, Yu Song, Wanqi Liang, Dabing Zhang
In organisms, aminoacyl-tRNA synthetases (aaRSs) play a housekeeping role in cellular protein synthesis, but little is understood about how these aaRSs are involved in organ development. Here we report that, in the model crop rice (Oryza sativa), a glutamyl-tRNA synthetase (OsERS1) maintains proper somatic cell organization and limits the over-proliferation of male germinal cells during early anther development. The expression of OsERS1 is specifically detectable in meristematic layer 2-derived (L2-d) cells of the early anther, and osers1 exhibits over-proliferation and disorganization of L2-d cells, producing fused lobes and extra germinal cells in early anthers...
May 2, 2018: Plant Physiology
Dong Wang, Yangyang Zhan, Dongbo Cai, Xiaoyun Li, Qin Wang, Shouwen Chen
The cyclodipeptide pulcherriminic acid synthesized by Bacillus licheniformis is an iron chelator and antagonizes certain pathogens by removing iron from the environment. But as the insoluble Fe-pulcherriminic acid complex cannot act as an iron carrier like siderophores, so excessive synthesized pulcherriminic acid causes iron starvation for the producer cells. At present, regulation of pulcherriminic acid synthesis and the mechanism by which B. licheniformis strikes a balance between biocontrol and self-protection from excessive iron removal remain unclear...
April 27, 2018: Applied and Environmental Microbiology
Kevin C Baldridge, Manasses Jora, Andre C Maranhao, Matthew M Quick, Balasubrahmanyam Addepalli, Jennifer S Brodbelt, Andrew D Ellington, Patrick A Limbach, Lydia M Contreras
Heterologous tRNA:aminoacyl tRNA synthetase pairs are often employed for noncanonical amino acid incorporation in the quest for an expanded genetic code. In this work, we investigated one possible mechanism by which directed evolution can improve orthogonal behavior for a suite of Methanocaldococcus jannaschii ( Mj) tRNATyr -derived amber suppressor tRNAs. Northern blotting demonstrated that reduced expression of heterologous tRNA variants correlated with improved orthogonality. We suspected that reduced expression likely minimized nonorthogonal interactions with host cell machinery...
April 25, 2018: ACS Synthetic Biology
Joshi Stephen, Sheela Nampoothiri, Aditi Banerjee, Nathanial J Tolman, Josef Martin Penninger, Ullrich Elling, Chukwuma A Agu, John D Burke, Kalpana Devadathan, Rajesh Kannan, Yan Huang, Peter J Steinbach, Susan A Martinis, William A Gahl, May Christine V Malicdan
Progressive microcephaly and neurodegeneration are genetically heterogenous conditions, largely associated with genes that are essential for the survival of neurons. In this study, we interrogate the genetic etiology of two siblings from a non-consanguineous family with severe early onset of neurological manifestations. Whole exome sequencing identified novel compound heterozygous mutations in VARS that segregated with the proband: a missense (c.3192G>A; p.Met1064Ile) and a splice site mutation (c.1577-2A>G)...
April 24, 2018: Human Genetics
Margaret A Schwarz, Daniel D Lee, Seamus Bartlett
Higher eukaryotes have developed extensive compartmentalization of amino acid (aa) - tRNA coupling through the formation of a multi-synthetase complex (MSC) that is composed of eight aa-tRNA synthetases (ARS) and three scaffold proteins: aminoacyl tRNA synthetase complex interacting multifunctional proteins (AIMP1, 2 and 3). Lower eukaryotes have a much smaller complex while yeast MSC consists of only two ARS (MetRS and GluRS) and one ARS cofactor 1 protein, Arc1p (Simos et al., 1996), the homolog of the mammalian AIMP1...
April 18, 2018: International Journal of Biochemistry & Cell Biology
Preyesh Stephen, Sheng Ye, Ming Zhou, Jian Song, Rongguang Zhang, En-Duo Wang, Richard Giegé, Sheng-Xiang Lin
Aminoacyl-tRNA synthetases are essential components in protein biosynthesis. Arginyl-tRNA synthetase (ArgRS) belongs to the small group of aaRSs requiring cognate tRNA for amino acid activation. The crystal structure of Escherichia coli (Eco) ArgRS has been solved in complex with tRNAArg at 3.0Å resolution. With this first bacterial tRNA complex, we are attempting to bridge the gap existing in structure-function understanding in prokaryotic tRNAArg recognition. The structure shows a tight binding of tRNA on the synthetase through the identity determinant A20 from the D-loop, a tRNA recognition snapshot never elucidated structurally...
April 17, 2018: Journal of Molecular Biology
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