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Expansion of bisindole biosynthetic pathways by combinatorial construction
Yi-Ling Du1, Katherine S Ryan1
1Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
ACS Synthetic Biology
|December 31, 2014
Summary
Scientists engineered a microbial platform to create novel bisindole compounds for drug discovery by redirecting natural product pathways. This approach generates new molecular diversity and aids in understanding enzyme functions for future catalyst development.
Area of Science:
- Natural Product Biosynthesis
- Synthetic Biology
- Medicinal Chemistry
Background:
- Cladoniamides are indolotryptoline natural products derived from indolocarbazole precursors.
- Existing pathways offer limited structural diversity for drug discovery.
Purpose of the Study:
- To develop a microbial platform for generating unnatural bisindoles.
- To enable drug discovery through pathway redirection and enzyme engineering.
Main Methods:
- Artificial redirection of the cladoniamide pathway using genes from related indolocarbazole pathways.
- Targeting glycosyltransferase, halogenase, and oxidoreductase enzymes.
- Engineering bisindole genes for novel compound generation.
Main Results:
- Successful generation of a series of novel unnatural bisindole compounds.
- Elucidation of substrate specificities for key enzymes.
- Demonstration of a versatile strategy for structural diversification.
Conclusions:
- The engineered microbial platform effectively produces novel bisindoles for drug discovery.
- Enzyme engineering and pathway redirection are powerful tools for natural product analog synthesis.
- The presented strategy can be applied to diversify other natural product families.
Keywords:
bisindole biosynthesiscombinatorial engineeringflavin-dependent monooxygenaseglycosyltransferasehalogenasesynthetic pathwaysMore Related Videos
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