RUI: BIOPOLYMER - BIObricks POLYketide Metabolic EngineeRing platform for unraveling the biosynthesis of higher anthracyclines

Ferris State University (Inc.), Big Rapids MI

Investigators

Abstract

Soil bacteria produce a variety of compounds. Some have medicinal value. A notable class of these molecules are referred to as anthracyclines (ACs). Anthracyclines treat several types of cancer. The objective of this project is to understand the regulation of AC production. Related enzymes and pathways will be "mixed and matched" to produce novel ACs with potentially novel anti-tumor properties. The project will be performed by undergraduates, directed by the principal investigator. It is expected that involving undergraduates in research will be effective in training them for careers in the biomanufacturing economy. Results will be communicated with the public through podcasts. The overall objective is to characterize the biosynthesis of glycosylated ACs. These are polyketide natural products with elaborate saccharide chains adorned with one or more amino-sugar and nitro-sugar moieties. Nitro-sugars are rarely observed on polyketides. The enzymes responsible for their biogenesis and attachment are poorly understood. Pathways will be brought together to yield new ACs. The central hypothesis is that the higher anthracycline pathways have shared evolution and enzymatic origins. This will be examined via comparative bioinformatics to inform pathway construction. This hypothesis will be functionally tested in two objectives: (1) two higher anthracycline pathways will be fully refactored in actinomycetes; and (2) the professor and his students will use combinatorial biosynthesis to synthesize new AC analogs expected to have anticancer and antibacterial activities. The ultimate goal is to develop design capabilities for synthesizing “new to nature” pharmaceuticals. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.