Engineering Plant Secondary Metabolite Biosynthesis in Microorganisms

ChEMS Seminar

Featuring Mattheos Koffas, Ph.D.
Assistant Professor, Chemical and Biological Engineering
University at Buffalo, The State University of New York

Location:  McDonald Douglas Auditorium (MDEA)

Abstract:
For several years, an important source for drug leads has been natural products - more than half of the drugs currently in clinical use are either natural products or their analogues. However, pharmaceutical companies have yet to fully endorse natural products over drugs developed through combinatorial chemistry citing availability issues as the main reason behind this. 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. We are particularly interested in the development of computational and experimental tools that will allow the efficient, high yield production of plant secondary metabolites such as flavonoid polyphenols.

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 result in the future in commercial viable processes for the synthesis of these important molecules. Combination of biochemical processes through the engineered microbial strains with classical mutasynthesis feed experiments have also led to the generation of novel flavonoid molecules with promising therapeutic properties. Furthermore, our group has 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.

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.

About the Speaker:
As a doctoral student at MIT(1994-2000), Koffas developed novel recombinant strains of Corynebacterium glutamicum for the high-yield production of amino acids using metabolic engineering approaches. As a visiting research scientist at DuPont’s Central Research and Development (2001-2002), he worked on the development of a new microbial process for converting natural gas into high-value chemicals such as carotenoids. His work included the isolation of an obligate methanotrophic strain and investigation of its central carbon metabolism. Within this context, he demonstrated for the first time the presence of a functional Embden-Meyerhoff-Parnas pathway in an obligate methanotroph. In 2002, he joined the Department of Chemical and Biological Engineering at the University at Buffalo, the State University of New York as a tenure-track Assistant Professor. Since then, he has established independent research that focuses on metabolic engineering of microorganisms for the efficient production of natural products with pharmaceutical and nutraceutical applications. It also focuses on the alteration of the chemistry of natural products with the purpose of generating new molecules with more potent or new therapeutic properties. His work at SUNY Buffalo has resulted in numerous publications in leading Journals in the field of applied microbiology and metabolic engineering and patents and has received funding from National (National Science Foundation), State (NY Center of Excellence in Bioinformatics) and Industrial (Degussa and Firstwave Technologies) sources.