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

Sci Rep. 2015 Aug 14;5:13160. doi: 10.1038/srep13160.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acyl-tRNA Synthetases / metabolism*
  • Angiogenesis Inhibitors / administration & dosage*
  • Angiogenesis Inhibitors / chemistry
  • Angiogenic Proteins / metabolism*
  • Animals
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Macrolides / antagonists & inhibitors*
  • Neovascularization, Physiologic / drug effects*
  • Neovascularization, Physiologic / physiology*
  • Zebrafish

Substances

  • Angiogenesis Inhibitors
  • Angiogenic Proteins
  • Macrolides
  • Amino Acyl-tRNA Synthetases

Associated data

  • PDB/4TTV