Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor

• DOI: 10.1038/srep13160
• Publication Date: 2015-08-14T11:41:01Z
• Authors: Adam C. Mirando; Pengfei Fang; Tamara F. Williams; Linda C. Baldor; Alan K. Howe; Alicia M. Ebert; Barrie Wilkinson; Karen M. Lounsbury; Min Guo; Christopher S. Fr...
• Keywords: Amino Acyl-tRNA Synthetases

Abstract Aminoacyl-tRNA synthetases (AARSs) catalyze an early step in protein synthesis, but also regulate diverse physiological processes animal cells. These include angiogenesis and human threonyl-tRNA synthetase (TARS) represents a potent pro-angiogenic AARS. Angiogenesis stimulation can be blocked by the macrolide antibiotic borrelidin (BN), which exhibits broad spectrum toxicity that has discouraged deeper investigation. Recently, less toxic variant (BC194) was identified potently inhibits angiogenesis. Employing biochemical, cell biological biophysical approaches, we demonstrate of BN its derivatives is linked to competition with threonine substrate at molecular level, stimulates amino acid starvation apoptosis. By separating from inhibition angiogenesis, direct role for TARS vascular development zebrafish could demonstrated. Bioengineered natural products are thus useful tools unmasking cryptic functions conventional enzymes regulation complex higher metazoans.