scholarly journals Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among N-benzylidene-N′-thiazol-2-yl-hydrazines

MedChemComm ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 2161-2169
Author(s):  
Oksana P. Kovalenko ◽  
Galyna P. Volynets ◽  
Mariia Yu. Rybak ◽  
Sergiy A. Starosyla ◽  
Olga I. Gudzera ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Target Activity ◽  
Dual Target

A screen of 37 compounds identified four inhibitors that exhibited dual on-target activity against Mycobacterium tuberculosis aminoacyl-tRNA synthetases.

scholarly journals Structure of Mycobacterium tuberculosis Phe-tRNA synthetase reveals ligand binding and two-stage tRNA recognition

2020 ◽  
Author(s):  
Karolina Michalska ◽  
Robert Jedrzejczak ◽  
Jacek Wower ◽  
Changsoo Chang ◽  
Beatriz Baragaña ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Trna Synthetase ◽  
Specific Amino Acid ◽  
Trna Synthetases ◽  
Trna Recognition ◽  
Aminoacyl Trna Synthetases ◽  
Global Spread ◽  
Modes Of Interaction ◽  
First Time

Abstract Tuberculosis, caused by Mycobacterium tuberculosis, responsible for ~1.5 million fatalities in 2018, is the deadliest infectious disease. Global spread of multidrug resistant TB is a public health threat. Aminoacyl-tRNA synthetases are plausible candidates as potential targets because they play pivotal roles in translating the DNA code into protein sequence by attaching specific amino acid to their cognate tRNAs. One of the best characterized synthetases is specific for L-Phe and tRNAPhe. Here we report structures of M. tuberculosis Phe-tRNA synthetase complexed with precursor tRNA and either phenylalanine or a phenylalanine adenylate analog, 5′-O-(N-phenylalanyl)sulfamoyl-adenosine. Crystallographic models for the first time reveal two modes of interaction with tRNA: an initial recognition via the anticodon loop and stem only and productive binding with interaction of the 3’ end of tRNAPhe with the adenylate site. We biochemically characterize the enzyme and provide the highest resolution, most complete view of the Phe-tRNA synthetase/tRNAPhe system to date.

scholarly journals Engineering aminoacyl-tRNA synthetases for use in synthetic biology

2020 ◽  
pp. 351-395
Author(s):  
Natalie Krahn ◽  
Jeffery M. Tharp ◽  
Ana Crnković ◽  
Dieter Söll
Keyword(s):  
Synthetic Biology ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases

scholarly journals Destruxin A Interacts with Aminoacyl tRNA Synthases in Bombyx mori

2021 ◽  
Vol 7 (8) ◽  
pp. 593
Author(s):  
Jingjing Wang ◽  
Alexander Berestetskiy ◽  
Qiongbo Hu
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Bombyx Mori ◽  
Metarhizium Anisopliae ◽  
Free Amino ◽  
Molecular Target ◽  
Trna Synthetases ◽  
Interaction Mode ◽  
Aminoacyl Trna Synthetases ◽  
Wide Range

Destruxin A (DA), a hexa-cyclodepsipeptidic mycotoxin produced by the entomopathogenic fungus Metarhizium anisopliae, exhibits insecticidal activities in a wide range of pests and is known as an innate immunity inhibitor. However, its mechanism of action requires further investigation. In this research, the interactions of DA with the six aminoacyl tRNA synthetases (ARSs) of Bombyx mori, BmAlaRS, BmCysRS, BmMetRS, BmValRS, BmIleRS, and BmGluProRS, were analyzed. The six ARSs were expressed and purified. The BLI (biolayer interferometry) results indicated that DA binds these ARSs with the affinity indices (KD) of 10−4 to 10−5 M. The molecular docking suggested a similar interaction mode of DA with ARSs, whereby DA settled into a pocket through hydrogen bonds with Asn, Arg, His, Lys, and Tyr of ARSs. Furthermore, DA treatments decreased the contents of soluble protein and free amino acids in Bm12 cells, which suggested that DA impedes protein synthesis. Lastly, the ARSs in Bm12 cells were all downregulated by DA stress. This study sheds light on exploring and answering the molecular target of DA against target insects.

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