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Naeem Khan, Asghari Bano, Mohammad Atikur Rahman, Bala Rathinasabapathi, Md Ali Babar
Genetic improvement for drought tolerance in chickpea requires a solid understanding of biochemical processes involved with different physiological mechanisms. The objective of this study is to demonstrate genetic variations in altered metabolic levels in chickpea varieties (tolerant and sensitive) grown under contrasting water regimes through UPLC-HRMS based untargeted metabolomic profiling. Chickpea plants were exposed to drought stress at the three-leaf stage for 25 days and the leaves were harvested at 14 days and 25 days after the imposition of drought stress...
March 13, 2018: Plant, Cell & Environment
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
Arwa M Amin, Lim Sheau Chin, Chin-Hoe The, Hamza Mostafa, Dzul Azri Mohamed Noor, Muhamad Ali S K Abdul Kader, Yuen Kah Hay, Baharudin Ibrahim
Dual antiplatelet therapy (DAPT) of clopidogrel and aspirin is crucial for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, some patients may endure clopidogrel high on treatment platelets reactivity (HTPR) which may cause thromboembolic events. Clopidogrel HTPR is multifactorial with some genetic and non-genetic factors contributing to it. We aimed to use nuclear magnetic resonance (1 H NMR) pharmacometabolomics analysis of plasma to investigate this multifactorial and identify metabolic phenotypes and pathways associated with clopidogrel HTPR...
March 8, 2018: European Journal of Pharmaceutical Sciences
Wanxin Li, Song Zhang, Xiaoyun Wang, Jing Yu, Zeqi Li, Wenxiong Lin, Xiangmin Lin
Many antibiotics are used to kill pathogenic Escherichia coli each year, resulting in an increase in the number of antibiotic-resistant strains. In this study, an integrated metabonomic-proteomic method was performed to systematically compare the profiles of metabolites and proteins with or without ciprofloxacin (CFLX) treatment. Proteomics identified 290 altered proteins including 143 with decreased and 147 increased expression, respectively. Metabonomics identified 65 altered metabolites including 58 and 7 with decreased and increased expression, respectively...
March 6, 2018: Journal of Proteomics
Anna Tjärnlund, Matteo Bottai, Ingrid E Lundberg
We have with great interest read the letter titled "Comments on the "2017 EULAR/ACR Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups". Points of concern", by Dr Castañeda et al published in your journal [1]. The authors discuss the antisynthetase syndrome (ASSD), a condition characterized by myositis, arthritis, interstitial lung disease (ILD), Raynaud's phenomenon and the presence of autoantibodies targeting aminoacyl transfer RNA synthetases, and the fact that this group was not included in the 2017 EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups [2]...
March 7, 2018: Arthritis & Rheumatology
Gabrielle Bourgeois, Jérôme Seguin, Morgan Babin, Pascal Belin, Mireille Moutiez, Yves Mechulam, Muriel Gondry, Emmanuelle Schmitt
Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNAs to catalyze the formation of two peptide bonds leading to cyclodipeptides that can be further used for the synthesis of diketopiperazines. It was shown that CDPSs fall into two subfamilies, NYH and XYP, characterized by the presence of specific sequence signatures. However, current understanding of CDPSs only comes from studies of enzymes from the NYH subfamily. The present study reveals the crystal structures of three CDPSs from the XYP subfamily. Comparison of the XYP and NYH enzymes shows that the two subfamilies mainly differ in the first half of their Rossmann fold...
March 2, 2018: Journal of Structural Biology
M Szelechowski, N Amoedo, E Obre, C Léger, L Allard, M Bonneu, S Claverol, D Lacombe, S Oliet, S Chevallier, G Le Masson, R Rossignol
Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively...
March 2, 2018: Scientific Reports
Laura Iannazzo, Matthieu Fonvielle, Emmanuelle Braud, Hubert Hřebabecký, Eliška Procházková, Radim Nencka, Christophe Mathé, Michel Arthur, Mélanie Etheve-Quelquejeu
We report here the synthetic route of two constrained dinucleotides and the determination of the sugar puckering by NMR analyses of the starting nucleosides. Enzymatic ligation to microhelix-RNAs provide access to tRNA analogues containing a 3' terminal A76 locked in South conformation. Biological evaluation of our tRNA analogues has been performed using amino-acyl tRNA-dependent transferase FemXWv , which mediates non-ribosomal incorporation of amino acids into the bacterial cell wall. We have shown that our tRNA analogues inhibited the aminoacyl transfer reaction catalyzed by FemXWv with IC50s of 10 and 8 μM...
February 27, 2018: Organic & Biomolecular Chemistry
Muriel Gondry, Isabelle B Jacques, Robert Thai, Morgan Babin, Nicolas Canu, Jérôme Seguin, Pascal Belin, Jean-Luc Pernodet, Mireille Moutiez
Cyclodipeptide synthases (CDPSs) use as substrates two amino acids activated as aminoacyl-tRNAs to synthesize cyclodipeptides in secondary metabolites biosynthetic pathways. Since the first description of a CDPS in 2002, the number of putative CDPSs in databases has increased exponentially, reaching around 800 in June 2017. They are likely to be involved in numerous biosynthetic pathways but the diversity of their products is still under-explored. Here, we describe the activity of 32 new CDPSs, bringing the number of experimentally characterized CDPSs to about 100...
2018: Frontiers in Microbiology
Sailendra Nath Sarma, Ammar Saleem, Jin-Yong Lee, Maki Tokumoto, Gi-Wook Hwang, Hing Man Chan, Masahiko Satoh
Cadmium (Cd) is a common environmental pollutant with known toxic effects on the kidney. Urinary metabolomics is a promising approach to study mechanism by which Cd-induced nephrotoxicity. The aim of this study was to elucidate the mechanism of Cd toxicity and to develop specific biomarkers by identifying urinary metabolic changes after a long-term of Cd exposure and with the critical concentration of Cd in the kidney. Urine samples were collected from wild-type 129/Sv mice after 67 weeks of 300 ppm Cd exposure and analyzed by ultra performance liquid chromatography connected with quadrupole time of flight mass spectrometer (UPLC-QTOF-MS) based metabolomics approach...
2018: Journal of Toxicological Sciences
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
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
Mónica Patricia Cala, María Teresa Agulló-Ortuño, Elena Prieto-García, Carolina González-Riano, Lucía Parrilla-Rubio, Coral Barbas, Carmen Vanesa Díaz-García, Antonia García, Cristina Pernaut, Jorge Adeva, María Carmen Riesco, Francisco Javier Rupérez, Jose Antonio Lopez-Martin
BACKGROUND: Cachexia is a metabolic syndrome that affects up to 50-80% of cancer patients. The pathophysiology is characterized by a variable combination of reduced food intake and abnormal metabolism, including systemic inflammation and negative protein and energy balance. Despite its high clinical significance, defined diagnostic criteria and established therapeutic strategies are lacking. The 'omics' technologies provide a global view of biological systems. We hypothesize that blood-based metabolomics might identify findings in cachectic patients that could provide clues to gain knowledge on its pathophysiology, and eventually postulate new therapeutic strategies...
February 20, 2018: Journal of Cachexia, Sarcopenia and Muscle
Tao Pan
Transfer RNA (tRNA) is present at tens of millions of transcripts in a human cell and is the most abundant RNA in moles among all cellular RNAs. tRNA is also the most extensively modified RNA with, on an average, 13 modifications per molecule. The primary function of tRNA as the adaptor of amino acids and the genetic code in protein synthesis is well known. tRNA modifications play multi-faceted roles in decoding and other cellular processes. The abundance, modification, and aminoacylation (charging) levels of tRNAs contribute to mRNA decoding in ways that reflect the cell type and its environment; however, how these factors work together to maximize translation efficiency remains to be understood...
February 20, 2018: Cell Research
Hongliang Qian, Qingqing Yao, Cui Tai, Zixin Deng, Jianhua Gan, Hong-Yu Ou
A type II toxin-antitoxin (TA) system, in which the toxin contains a Gcn5-related N-acetyltransferase (GNAT) domain, has been characterized recently. GNAT toxin acetylates aminoacyl-tRNA and blocks protein translation. It is abolished by the cognate antitoxin that contains the ribbon-helix-helix (RHH) domain. Here, we present an experimental demonstration of the interaction of the GNAT-RHH complex with TA promoter DNA. First, the GNAT-RHH TA locus kacAT was found in Klebsiella pneumoniae HS11286, a strain resistant to multiple antibiotics...
February 20, 2018: Molecular Microbiology
David L Niquille, Douglas A Hansen, Takahiro Mori, David Fercher, Hajo Kries, Donald Hilvert
Biosynthetic modification of nonribosomal peptide backbones represents a potentially powerful strategy to modulate the structure and properties of an important class of therapeutics. Using a high-throughput assay for catalytic activity, we show here that an L-Phe-specific module of an archetypal nonribosomal peptide synthetase can be reprogrammed to accept and process the backbone-modified amino acid (S)-β-Phe with near-native specificity and efficiency. A co-crystal structure with a non-hydrolysable aminoacyl-AMP analogue reveals the origins of the 40,000-fold α/β-specificity switch, illuminating subtle but precise remodelling of the active site...
March 2018: Nature Chemistry
Junhong Choi, Gabriele Indrisiunaite, Hasan DeMirci, Ka-Weng Ieong, Jinfan Wang, Alexey Petrov, Arjun Prabhakar, Gideon Rechavi, Dan Dominissini, Chuan He, Måns Ehrenberg, Joseph D Puglisi
Chemical modifications of mRNA may regulate many aspects of mRNA processing and protein synthesis. Recently, 2'-O-methylation of nucleotides was identified as a frequent modification in translated regions of human mRNA, showing enrichment in codons for certain amino acids. Here, using single-molecule, bulk kinetics and structural methods, we show that 2'-O-methylation within coding regions of mRNA disrupts key steps in codon reading during cognate tRNA selection. Our results suggest that 2'-O-methylation sterically perturbs interactions of ribosomal-monitoring bases (G530, A1492 and A1493) with cognate codon-anticodon helices, thereby inhibiting downstream GTP hydrolysis by elongation factor Tu (EF-Tu) and A-site tRNA accommodation, leading to excessive rejection of cognate aminoacylated tRNAs in initial selection and proofreading...
February 19, 2018: Nature Structural & Molecular Biology
Denis Susorov, Nikita Zakharov, Ekaterina Shuvalova, Alexander Ivanov, Tatiana Egorova, Alexey Shuvalov, Ivan N Shatsky, Elena Alkalaeva
During protein synthesis, a ribosome moves along the mRNA template and, using aminoacyl-tRNAs, decodes the template nucleotide triplets to assemble a protein amino acid sequence. This movement is accompanied by shifting of mRNA-tRNA complexes within the ribosome in a process called translocation. In living cells, this process proceeds in a unidirectional manner, bringing the ribosome to the 3'-end of mRNA, and is catalyzed by the GTPase translation elongation factor 2 (EF-G in prokaryotes, eEF2 in eukaryotes)...
February 16, 2018: Journal of Biological Chemistry
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