Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase

Abstract

The polyketide natural product borrelidin displays antibacterial, antifungal, antimalarial, anticancer, insecticidal and herbicidal activities through the selective inhibition of threonyl-tRNA synthetase (ThrRS). How borrelidin simultaneously attenuates bacterial growth and suppresses a variety of infections in plants and animals is not known. Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth ‘orthogonal’ subsite created as a consequence of binding. Thus, borrelidin competes with all three aminoacylation substrates, providing a potent and redundant mechanism to inhibit ThrRS during protein synthesis. These results highlight a surprising natural design to achieve the quadrivalent inhibition of translation through a highly conserved family of enzymes.

Borrelidin Isolated from <i>Streptomyces</i> sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells <i>via</i> Several Factors Including GATA-Binding Protein 3

“…Pharmacological studies have revealed that borrelidin exhibits anti-malarial, anti-angiogenesis and antifungal activities, [33][34][35] and borrelidin is also known as a strong inhibitor of threonyl-tRNA synthetase. 36,37) Although a variety of biological activity has been reported, there are no reports related to anti-obesity effect of borrelidin.…”

Design, synthesis and molecular docking of salicylic acid derivatives containing metronidazole as a new class of antimicrobial agents

“…4 So, inhibitors of AARSs have been used as medicine or rigorously tested in clinical trials for therapeutic applications in microbial infections, such as, the natural product mupirocin, an inhibitor of Isoleucyl-tRNA synthetase (IleRS), is approved as a topical treatment for bacterial skin infections. 7 Tyrosyl-tRNA synthetase (TyrRs) is one of the 20 Aminoacyl-tRNA synthetases and plays an important role in protein synthesis. 8 Nitroimidazole derivatives have exhibited broad variety biological activities, particularly antibacterial activity.…”

Chemoselective enrichment as a tool to increase access to bioactive natural products: Case study borrelidin

“…14,15 Chloroquine and artemisinin have been critical treatments for this infection, unfortunately resistance to both drugs has arisen. 16 Borrelidin inhibits threonine-tRNA synthetase (ThrRS), preventing the amino acid activation step and halting protein synthesis 17 and is effective against malaria, including drug-resistant strains. 12,18 Unfortunately, borrelidin is not selective for the malarial ThrRS over the human homolog.…”