V. M. Dan, V. J S, Sandesh C J
Feb 14, 2020
Citations
1
Influential Citations
13
Citations
Quality indicators
Journal
ACS chemical biology
Abstract
Rediscovery of known compounds and time consumed in identification, especially high molecular weight compounds with complex structure, have letdown interest in drug discovery. In this study, Whole-genome analysis of microbe and Global Natural Products Social (GNPS) Molecular Networking helped in initial understanding of possible compounds produced by the microbe. Genome data revealed ten biosythethic gene clusters that encode for secondary metabolites with anticancer potential. NMR analysis of pure compound revealed presence of a four-ringed benz[a]anthracene, thus confirming angucycline, molecular networking further confirmed production of this class of compounds. Type II polyketide synthase gene identified in microbial genome matched with Urdamycin cluster by BLAST analysis. These information led to ease in identification of Urdamycin E and a novel natural derivative, Urdamycin V, purified from Streptomyces sp OA293. Urdamycin E (Urd E) induced apoptosis and autophagy in cancer cell lines. Urd E exerted anticancer action through inactivation of mTOR complex by preventing phosphorylation at Ser 2448 and Ser 2481 of mTORC1 and mTORC2, respectively. Significant reduction in phosphorylation of the major downstream regulators of both mTORC1 (p70s6k and 4e-bp1) and mTORC2 (Akt) were observed thus further confirming complete inhibition of mTOR pathway. Urd E presents itself as a novel mTOR inhibitor that employs a novel mechanism in mTOR pathway inhibition.