cb0c00026_si_001.pdf (1.07 MB)
Molecular Networking and Whole-Genome Analysis Aid Discovery of an Angucycline That Inactivates mTORC1/C2 and Induces Programmed Cell Death
journal contribution
posted on 2020-02-25, 15:35 authored by Vipin Mohan Dan, Vinodh J S, Sandesh C J, Rahul Sanawar, Asha Lekshmi, R. Ajay Kumar, T. R. Santhosh Kumar, Uday Kiran Marelli, Syed G. Dastager, M. Radhakrishna PillaiRediscovery
of known compounds and time consumed in identification,
especially high molecular weight compounds with complex structure,
have let down 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 10 biosythethic gene clusters
that encode for secondary metabolites with anticancer potential. NMR
analysis of the pure compound revealed the presence of a four-ringed
benz[a]anthracene, thus confirming angucycline; molecular networking
further confirmed production of this class of compounds. The type
II polyketide synthase gene identified in the microbial genome was
matched with the urdamycin cluster by BLAST analysis. This 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 the
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 the mTOR pathway. Urd E presents itself as a novel mTOR inhibitor
that employs a novel mechanism in mTOR pathway inhibition.
History
Usage metrics
Categories
Keywords
compoundnovel mTOR inhibitorOA 293. Urdamycin EmicrobemTOR pathway inhibitionGNPSphosphorylationidentificationurdamycinnetworkingtype II polyketide synthase geneNMRSercancer cell lines10 biosythethic gene clustersgenomemTORC 1Urd EanalysisInduces Programmed Cell Death RediscoveryanticancerBLASTGlobal Natural Products SocialWhole-Genome Analysis Aid Discovery
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC