Engineering Plant Secondary Metabolite Biosynthesis In Microorganisms

For several years, natural products have been an important source for drug leads: more than half of the drugs currently in clinical use are either natural products or their analogues with a significant fraction of these compounds derived from plant sources. Our group focuses on utilizing the richness, versatility but also simplicity of microbial organisms in order to make them ideally suited to convert cheap, renewable resources into high-value, high-quality chemicals with enormous potential as nutraceuticals and pharmaceuticals.

For the purpose of reprogramming the cellular network in order to achieve optimal phenotypes supporting high-yield production, we have developed in silico models of the genome-wide metabolism of the two industrially important microorganisms, namely Escherichia coli and Saccharomyces cerevisiae. Through the application of Metabolic Flux Analysis, we can predict genetic modifications such as deletions and gene expression attenuations that lead to dramatic increases in production levels. Such Systems Biology approaches, in combination with traditional genetic engineering  have resulted in robust production levels that can provide commercially viable processes for the synthesis of important molecules, in particular ones that belong to the plant polyphenol category. Combination of biochemical processes through the engineered microbial strains with classical mutasynthesis feeding experiments have also led to the generation of novel polyphenol molecules with promising therapeutic properties, in particular antifungal activities. Our group has further developed protein engineering methodologies that allow the functional expression in prokaryotes of plant P450 monooxygenases. This is a very important group of enzymes that allows the functionalization of natural products and enhancement of their potential as therapeutics. At the same time, their functional expression in simple prokaryotes remains an engineering conundrum due to their complex biochemistry. In combination with high-throughput screening methods, also developed by our group, such protein engineering methods have further been used for improving production yields.

Overall, our work has allowed us to develop microbial Systems Biology and Metabolic Engineering approaches for the efficient production of natural products that can be extended to other small molecules of pharmaceutical and industrial importance.