Trna Synthetase
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ACS Omega ◽  
2021 ◽  
Author(s):  
Mariia Yu. Rybak ◽  
Olga I. Gudzera ◽  
Oksana B. Gorbatiuk ◽  
Mariia O. Usenko ◽  
Sergiy M. Yarmoluk ◽  
...  

2021 ◽  
Author(s):  
Adekunle Babjide Rowaiye ◽  
Akwoba Joseph Ogugua ◽  
Gordon Ibeanu ◽  
Doofan Bur ◽  
Osaretin Benjamin Ogbeide ◽  
...  

AbstractBackgroundBrucellosis is an infectious disease caused by bacteria of the genus Brucella. Although it is the most common zoonosis worldwide, there are increasing reports of drug resistance and cases of relapse after long term treatment with the existing drugs of choice. This study therefore aims at identifying possible natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach.MethodsUsing PyRx 0.8 virtual screening software, the target was docked against a library of natural compounds obtained from edible African plants. The compound, 2-({3-[(3,5-dichlorobenzyl) amino] propyl} amino) quinolin-4(1H)-one (OOU) which is a co-crystallized ligand with the target was used as the reference compound. Screening of the molecular descriptors of the compounds for bioavailability, pharmacokinetic properties, and bioactivity was performed using the SWISSADME, pkCSM, and Molinspiration web servers respectively. The Fpocket and PLIP webservers were used to perform the analyses of the binding pockets and the protein ligand interactions. Analysis of the time-resolved trajectories of the Apo and Holo forms of the target was performed using the Galaxy and MDWeb servers. The lead compounds, Strophanthidin and Isopteropodin are present in Corchorus olitorius and Uncaria tomentosa (cat-claw) plants respectively.ResultsIsopteropodin had a binding affinity score of -8.9 kcal / ml with the target and had 17 anti-correlating residues in pocket 1 after molecular dynamics simulation. The complex formed by Isopteropodin and the target had a total RMSD of 4.408 and a total RMSF of 9.8067. However, Strophanthidin formed 3 hydrogen bonds with the target at ILE21, GLY262 and LEU294, and induced a total RMSF of 5.4541 at Pocket 1.ConclusionOverall, Isopteropodin and Strophanthidin were found to be better drug candidates than OOU and they showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1, hence abilities to treat brucellosis. In vivo and in vitro investigations are needed to further evaluate the efficacy and toxicity of the lead compounds.Author SummaryStrophanthidin and Isopteropodin showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1Both compounds can be used to treat brucellosis.Both compounds showed potentials of being safe to use in humans.


2021 ◽  
pp. 2101554
Author(s):  
Alice Hadchouel ◽  
David Drummond ◽  
Clément Pontoizeau ◽  
Laura Aoust ◽  
Maria-Margarita Hurtado Nedelec ◽  
...  

IntroductionPulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease.MethodsFour patients received methionine supplementation and were followed for respiratory, hepatic, growth, and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species (ROS) production by patient monocytes before and after methionine supplementation was also studied.ResultsMethionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material, and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or non-invasive ventilation could be weaned off within 60 days. Liver dysfunction, inflammation, and growth delay also improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes.ConclusionMethionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.


2021 ◽  
Author(s):  
Hong Zhang ◽  
Jiang Wu ◽  
Zhihui Lyu ◽  
Jiqiang Ling

Abstract Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that provide the ribosome with aminoacyl-tRNA substrates for protein synthesis. Mutations in aaRSs lead to various neurological disorders in humans. Many aaRSs utilize editing to prevent error propagation during translation. Editing defects in alanyl-tRNA synthetase (AlaRS) cause neurodegeneration and cardioproteinopathy in mice and are associated with microcephaly in human patients. The cellular impact of AlaRS editing deficiency in eukaryotes remains unclear. Here we use yeast as a model organism to systematically investigate the physiological role of AlaRS editing. Our RNA sequencing and quantitative proteomics results reveal that AlaRS editing defects surprisingly activate the general amino acid control pathway and attenuate the heatshock response. We have confirmed these results with reporter and growth assays. In addition, AlaRS editing defects downregulate carbon metabolism and attenuate protein synthesis. Supplying yeast cells with extra carbon source partially rescues the heat sensitivity caused by AlaRS editing deficiency. These findings are in stark contrast with the cellular effects caused by editing deficiency in other aaRSs. Our study therefore highlights the idiosyncratic role of AlaRS editing compared with other aaRSs and provides a model for the physiological impact caused by the lack of AlaRS editing.


2021 ◽  
Author(s):  
Jinyong Shu ◽  
Yi Gao ◽  
Guifeng Zhang ◽  
Pan Luo

Abstract BackgroundAlthough glutamyl-prolyl tRNA synthetase (EPRS) mRNA is overexpressed and plays an important role in most tumors, its role in the development and progression of hepatocellular carcinoma (HCC) remains unclear. MethodsThe expression of EPRS in tumor and adjacent tissues was queried using TIMER and The Cancer Genome Atlas. The results were validated using the real-time reverse transcription polymerase chain reaction on RNA extracted from tumor and adjacent non-tumor samples from 10 HCC patients.ResultsUsing bioinformatics analysis, we found that EPRS mRNA was overexpressed in HCC tumor tissues, and the expression level of EPRS mRNA in The Cancer Genome Atlas database was significantly correlated with tumor size (p = 0.0010), histological grade (p = 0.0002), TNM stage (p = 0.0001), and vascular invasion (p = 0.0123) of HCC. The Kaplan-Meier survival analysis demonstrated that the expression of EPRS mRNA was associated with poor overall survival (p = 0.0004). Ten pairs of tumor and adjacent normal tissues were collected from patients with HCC, and the expression of EPRS mRNA was verified. The results showed that the EPRS mRNA level in HCC tissues was higher than that in paracancerous tissues (p = 0.0401). ConclusionOverexpression of EPRS mRNA may be associated with tumorigenesis and the progression of HCC.


2021 ◽  
Author(s):  
Haissi Cui ◽  
Jolene K. Diedrich ◽  
Douglas C. Wu ◽  
Justin J. Lim ◽  
Ryan M. Nottingham ◽  
...  

SummaryCells respond to perturbations such as inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has long known connections to the inflammatory response. Here we show that depletion of arginine during inflammation decreased levels of arginyl-tRNA synthetase (ArgRS) in the nucleus. We found that nuclear ArgRS interacted with serine/arginine repetitive matrix protein 2 (SRRM2) in membrane-less, condensate-like, SRRM2-dependent nuclear speckles. This interaction impeded SRRM2 speckle trafficking and resulted in changes in alternative mRNA splicing. Splice site usage was regulated in opposite directions by ArgRS and SRRM2. These ArgRS- and SRRM2-dependent splicing changes cumulated in synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings delineate a novel mechanism whereby a tRNA synthetase responds to a metabolic change and modulates the splicing machinery via condensate trafficking for cellular responses to inflammatory injury.


Science ◽  
2021 ◽  
Vol 373 (6559) ◽  
pp. 1156-1161 ◽  
Author(s):  
E. L. Spaulding ◽  
T. J. Hines ◽  
P. Bais ◽  
A. L. D. Tadenev ◽  
R. Schneider ◽  
...  

Science ◽  
2021 ◽  
Vol 373 (6559) ◽  
pp. 1161-1166 ◽  
Author(s):  
Amila Zuko ◽  
Moushami Mallik ◽  
Robin Thompson ◽  
Emily L. Spaulding ◽  
Anne R. Wienand ◽  
...  

2021 ◽  
pp. 101203
Author(s):  
Danni Jin ◽  
Sheree A. Wek ◽  
Nathan T. Kudlapur ◽  
William A. Cantara ◽  
Marina Bakhtina ◽  
...  

2021 ◽  
Vol 16 (9) ◽  
pp. 1934578X2110311
Author(s):  
Muhammad Alamzeb ◽  
Saqib Ali ◽  
Mamoon-Ur-Rashid ◽  
Behramand Khan ◽  
Ihsanullah ◽  
...  

Leishmaniases are a spectrum of poverty-linked neglected parasitic diseases that are endemic in 88 countries around the globe and affect millions of people every year. Currently available chemotherapeutic options are inadequate due to side effects, high cost, prolonged treatment, and parasite resistance. Thus, there is an existing need to develop new potent and safer leishmanicidal drugs. Considering the folkloric antiulcer and leishmanicidal use of the genus Berberis and its alkaloids, 5 reported alkaloids, namely berberine (1), palmatine (2), columbamine (3), 8-trichloromethyldihydroberberine (4), and jatrorrhizine (5), were isolated from the roots of Berberis glaucocarpa using classical (column and preparative chromatography) and modern isolation techniques (Sephadex LH-20). Their structures were elucidated and established from 1D and 2D spectroscopic data. The isolated alkaloids displayed excellent antileishmanial potential with IC50 values ranging from 1.50 to 2.56 µM: 1 (1.50 ± 0.53 µM), 2 (2.31 ± 0.37 µM), 3 (2.56 ± 0.48 µM), 4 (1.40 ± 0.90 µM), 5 (2.44 ± 1.34 µM). While the IC50 value for the standard drug (Amphotericin-B) was found to be 1.08 ± 0.95 µM. All of the isolated alkaloids displayed excellent antileishmanial potential as well as minimal cytotoxicity against THP-1 monocytic cells. Molecular docking analysis has revealed Leishmania N-myristoyl transferase, methionyl-tRNA synthetase, pteridine reductase 1, oligopeptidase B, tyrosyl-tRNA synthetase, and/or glycerol-3-phosphate dehydrogenase to be potential protein targets for the alkaloids.


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