Evolutionary Limitation and Opportunities for Developing tRNA Synthetase Inhibitors with 5-Binding-Mode Classification

Abstract

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that catalyze the transfer of amino acids to their cognate tRNAs as building blocks for translation. Each of the aaRS families plays a pivotal role in protein biosynthesis and is indispensable for cell growth and survival. In addition, aaRSs in higher species have evolved important non-translational functions. These translational and non-translational functions of aaRS are attractive for developing antibacterial, antifungal, and antiparasitic agents and for treating other human diseases. The interplay between amino acids, tRNA, ATP, EF-Tu and non-canonical binding partners, had shaped each family with distinct pattern of key sites for regulation, with characters varying among species across the path of evolution. These sporadic variations in the aaRSs offer great opportunity to target these essential enzymes for therapy. Up to this day, growing numbers of aaRS inhibitors have been discovered and developed. Here, we summarize the latest developments and structural studies of aaRS inhibitors, and classify them with distinct binding modes into five categories.

Drugging tRNA aminoacylation

“…Within the active site of each aaRS catalytic domain, there exist three distinct binding pockets responsible for recognition of amino acid, adenylate, and tRNA moieties ( Fig. 1) [22,27]. While some aaRS inhibitors target the separate editing domain, the majority bind one or more pockets within the catalytic domain [16,22].…”

“…1) [22,27]. While some aaRS inhibitors target the separate editing domain, the majority bind one or more pockets within the catalytic domain [16,22]. Structurally, most aaRS inhibitor antibiotics act as non-cleavable mimics of AA-AMP, which is the natural intermediate produced during aminoacylation (see Scheme 1) [16,22].…”

“…While some aaRS inhibitors target the separate editing domain, the majority bind one or more pockets within the catalytic domain [16,22]. Structurally, most aaRS inhibitor antibiotics act as non-cleavable mimics of AA-AMP, which is the natural intermediate produced during aminoacylation (see Scheme 1) [16,22]. The best described example of such an inhibitor is mupirocin, which is one of only three approved aaRS inhibitor antibiotics prescribed for human or veterinary use (alongside halofuginone and tavaborole) [29][30][31].…”

“…Here we review available data regarding known aminoacylation inhibitors, as well as key determinants in both the aaRS and tRNA macromolecules that determine the specificity and strength of the aaRS-tRNA interaction. We focus on the molecular mechanisms of binding, turnover, and specificity in the aaRS-tRNA interaction with respect to drug design, utilizing the increasing body of available of genomic data, in vitro mutational analysis, and structural information [21,22].…”

Aminoacyl tRNA Synthetases as Malarial Drug Targets: A Comparative Bioinformatics Study

“…Aminoacyl tRNA synthetases (aaRSs) are a group of key enzymes in protein translation pathway; they catalyze the first reaction, where an amino acid is added to the cognate tRNA molecule in the presence of ATP and magnesium (Mg 2+ ) ions. This reaction takes place in two steps; first ATP activates the amino acid through formation of aminoacyl-adenylate intermediate, while the second step involves ligation of the adenylate intermediate to the cognate tRNA molecule through a covalent bond generating AMP [8,9,18]. Although the canonical function of these enzymes is to add amino acids to tRNA for translation and they are highly conserved in their catalytic domains, in general aaRSs show sequence, structural and functional diversity across organisms [19].…”