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

Mirando AC, Fang P, Williams TF, Baldor LC, Howe AK, Ebert AM, Wilkinson B, Lounsbury KM, Guo M, Francklyn CS - Sci Rep (2015)

Bottom Line: These include angiogenesis, and human threonyl-tRNA synthetase (TARS) represents a potent pro-angiogenic AARS.Recently, a less toxic variant (BC194) was identified that potently inhibits angiogenesis.Bioengineered natural products are thus useful tools in unmasking the cryptic functions of conventional enzymes in the regulation of complex processes in higher metazoans.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Vermont.

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.

No MeSH data available.


Related in: MedlinePlus

Structures of macrolides used in this study.Structures of borrelidin BN (1), BC194 (2), and BC220 (3).
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f1: Structures of macrolides used in this study.Structures of borrelidin BN (1), BC194 (2), and BC220 (3).

Mentions: A class of potent natural products that inhibit the pro-angiogenic properties of TARS represent valuable tools to characterize this function. Borrelidin (BN) (1, Fig. 1) an 18-membered macrolide antibiotic produced in Streptomyces rocheii, is a potent antibacterial, antiviral, and antifungal agent2122. BN is also a potent anti-malarial2324 and inhibits tube formation in a rat aortic angiogenesis model and metastasis in a mouse model of melanoma25. The isolation of resistant bacterial strains2627 and Chinese hamster ovary cell lines with selective gene amplification28 demonstrated that the principal target of borrelidin in bacteria and eukaryotes is threonyl-tRNA synthetase. By contrast, archaeal ThrRSs are highly resistant to BN, a consequence of the significant divergence between these enzymes from those of other kingdoms2930. At higher concentrations, BN is known to affect other cellular targets, including the spliceosome associated factor FBP2131. Despite its potency, the cytotoxicity of BN to normal epithelial cells has created a significant barrier to any clinical application32.


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

Mirando AC, Fang P, Williams TF, Baldor LC, Howe AK, Ebert AM, Wilkinson B, Lounsbury KM, Guo M, Francklyn CS - Sci Rep (2015)

Structures of macrolides used in this study.Structures of borrelidin BN (1), BC194 (2), and BC220 (3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4536658&req=5

f1: Structures of macrolides used in this study.Structures of borrelidin BN (1), BC194 (2), and BC220 (3).
Mentions: A class of potent natural products that inhibit the pro-angiogenic properties of TARS represent valuable tools to characterize this function. Borrelidin (BN) (1, Fig. 1) an 18-membered macrolide antibiotic produced in Streptomyces rocheii, is a potent antibacterial, antiviral, and antifungal agent2122. BN is also a potent anti-malarial2324 and inhibits tube formation in a rat aortic angiogenesis model and metastasis in a mouse model of melanoma25. The isolation of resistant bacterial strains2627 and Chinese hamster ovary cell lines with selective gene amplification28 demonstrated that the principal target of borrelidin in bacteria and eukaryotes is threonyl-tRNA synthetase. By contrast, archaeal ThrRSs are highly resistant to BN, a consequence of the significant divergence between these enzymes from those of other kingdoms2930. At higher concentrations, BN is known to affect other cellular targets, including the spliceosome associated factor FBP2131. Despite its potency, the cytotoxicity of BN to normal epithelial cells has created a significant barrier to any clinical application32.

Bottom Line: These include angiogenesis, and human threonyl-tRNA synthetase (TARS) represents a potent pro-angiogenic AARS.Recently, a less toxic variant (BC194) was identified that potently inhibits angiogenesis.Bioengineered natural products are thus useful tools in unmasking the cryptic functions of conventional enzymes in the regulation of complex processes in higher metazoans.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Vermont.

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.

No MeSH data available.


Related in: MedlinePlus