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Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond
Front Immunol 2022 May 13;13:866087.PMID:35634293DOI:10.3389/fimmu.2022.866087.
Anti-synthetase syndrome (ASSD) is an autoimmune disease characterized by the presence of autoantibodies targeting one of several aminoacyl t-RNA synthetases (aaRSs) along with clinical features including interstitial lung disease, myositis, Raynaud's phenomenon, arthritis, mechanic's hands, and fever. The family of aaRSs consists of highly conserved cytoplasmic and mitochondrial enzymes, one for each amino acid, which are essential for the RNA translation machinery and protein synthesis. Along with their main functions, aaRSs are involved in the development of immune responses, regulation of transcription, and gene-specific silencing of translation. During the last decade, these proteins have been associated with cancer, neurological disorders, infectious responses, and autoimmune diseases including ASSD. To date, several aaRSs have been described to be possible autoantigens in different diseases. The most commonly described are histidyl (HisRS), threonyl (ThrRS), alanyl (AlaRS), glycyl (GlyRS), isoleucyl (IleRS), asparaginyl (AsnRS), phenylalanyl (PheRS), tyrosyl (TyrRS), lysyl (LysRS), glutaminyl (GlnRS), tryptophanyl (TrpRS), and seryl (SerRS) tRNA synthetases. Autoantibodies against the first eight autoantigens listed above have been associated with ASSD while the rest have been associated with other diseases. This review will address what is known about the function of the aaRSs with a focus on their autoantigenic properties. We will also describe the anti-aaRSs autoantibodies and their association to specific clinical manifestations, and discuss their potential contribution to the pathogenesis of ASSD.
Bicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase
Nat Commun 2022 Jan 24;13(1):459.PMID:35075105DOI:10.1038/s41467-022-28108-y.
Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world's human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a structural basis for rational design of improved analogs. Favorable pharmacokinetic properties of a lead compound provide excellent protection from acute infection and partial protection from chronic infection in an immunocompromised mouse model of toxoplasmosis. Collectively, PheRS inhibitors of the bicyclic azetidine series offer promise for treatment of chronic toxoplasmosis.
RNA binding small molecules: studies on t-RNA binding by cytotoxic plant alkaloids berberine, palmatine and the comparison to ethidium
Biophys Chem 2007 Feb;125(2-3):508-20.PMID:17156912DOI:10.1016/j.bpc.2006.11.001.
The interaction of two natural protoberberine plant alkaloids berberine and palmatine with t-RNA(phe) was studied using various biophysical techniques and the data was compared with the binding of the classical DNA intercalator, ethidium. The results of optical thermal melting, differential scanning calorimetry and circular dichroism characterized the native cloverleaf structure of t-RNA under the conditions of the study. The strong binding of the alkaloids and ethidium to t-RNA was revealed from the absorption and fluorescence studies. The salt dependence of the binding constants enabled the dissection of the binding free energy to electrostatic and non-electrostatic contributions. This analysis revealed a surprisingly large favourable component of the non-electrostatic contribution to the binding of these charged alkaloids and ethidium to t-RNA. Isothermal titration calorimetric studies revealed that the binding of both the alkaloids is driven by a moderately favourable enthalpy decrease and a moderately favourable entropy increase while that of ethidium is driven by a large favourable enthalpy decrease. Taken together, the results suggest that the binding of these alkaloid molecules on the t-RNA structure appears to be mostly by partial intercalation while ethidium intercalates to the t-RNA. These results reveal the molecular aspects on the interaction of these alkaloids to t-RNA.
Exploring the interaction of Azure dyes with t-RNA by hybrid spectroscopic and computational approaches and its applications toward human lung cancer cell line
Int J Biol Macromol 2018 Jul 1;113:1052-1061.PMID:29501842DOI:10.1016/j.ijbiomac.2018.02.164.
In the present study, in depth characterization of binding aspects of Azure A (AZA) and Azure B (AZB) with transfer Ribonucleic acid (t-RNA) from Escherichia coli (E.coli) is investigated using spectroscopic techniques. The absorbance and fluorescence properties of these dyes have been remarkably changed upon binding with t-RNA. Significant changes in the absorption maxima of the dyes evidence the t-RNA induced metachromasy and the binding clearly revealed the high affinity of AZA and AZB to t-RNA. Strong emission polarization of the bound dyes and strong energy transfer from the guanine base pairs of t-RNA suggested intercalative binding interaction. The stoichiometry of AZA and AZB with t-RNA complexes are determined by the Benesi-Hildebrand plot from emission data. The negative values of free energy change indicated the involvement of hydrophobic forces and noncovalent interactions in the complexation of both the dyes with t-RNA. The 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay in A-549 human lung cancer cell lines reveals that binding of t-RNA reduces the toxicity of AZA and AZB. The utility of the present work explores the potential binding applicability of these dyes to t-RNA for their development as effective therapeutic agents and its target at molecular level for the treatment of diseases like cancer.
RNA targeting through binding of small molecules: Studies on t-RNA binding by the cytotoxic protoberberine alkaloid coralyne
Mol Biosyst 2009 Mar;5(3):244-54.PMID:19225615DOI:10.1039/b816480k.
Interaction of the protoberberine alkaloid coralyne with t-RNA(phe) was investigated using various biophysical techniques. Results of absorption and fluorescence studies revealed that the alkaloid binds to t-RNA exhibiting positive cooperativity. Isothermal titration calorimetry results suggested that the binding of the alkaloid was predominantly enthalpy driven with a smaller favourable entropy term. A surprisingly large favourable component for non-electrostatic contribution to the binding of coralyne to t-RNA was revealed from salt dependence data and the dissection of the free energy. The alkaloid enhanced the thermal stability of t-RNA and the binding affinity values obtained from optical thermal melting data was in agreement with that from calorimetry. The heat capacity change of -125 cal mol(-1) K(-1) and the observed significant enthalpy-entropy compensation phenomenon confirmed the involvement of multiple weak noncovalent interactions. Circular dichroism studies provided evidence for significant perturbation of the t-RNA structure with concomitant induction of optical activity in the bound achiral alkaloid molecules. Binding isotherms generated from circular dichroic data confirmed the cooperative binding mode of the alkaloid as deduced from spectroscopic data. Docking studies provided further insights into the partially intercalated state of coralyne inside the t-RNA structure. This study presents a complete binding and thermodynamic profile of coralyne interaction to t-RNA.
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