Sattely Lab: Applications and Discovery of Plant Chemistry
Plants provide ~10% of clinically used therapeutics, form the basis of our diet, and are a promising source of renewable energy. Despite their major impact on human health and the energy sector, many of the ways we use plants are ripe for disruption: numerous drugs are still isolated from difficult-to-cultivate native plants, the chemistry of dietary crops is poorly understood and unoptimized, and one of the most abundant biopolymers on earth – lignocellulose – is largely underutilized. The merger of engineering and plant chemistry holds promise for a great leap forward in how we use plants; the central challenge is identifying the genes that make up plant metabolic pathways as the first step towards engineering new chemistry. Our lab is focused on three grand challenges in the area of plant chemistry, described below. Each of these objectives can be addressed using designed metabolic pathways but only with the right set of enzyme catalysts. For example, with a complete set of biosynthetic enzymes, plant metabolites of therapeutic interest can be mass-produced in an easily cultivated plant like tobacco. Molecules that promote fitness in one plant could be engineered into another by genome editing. Finally, lignin could be processed into valuable aromatics using whole cell biocatalysts engineered with a specific collection of microbial enzymes.
(1) Manufacturing and engineering molecules from plants. Molecules from plants play a critical role in human health as drugs and dietary nutrients. 10% of the WHO essential medicines are plant natural products or derivatives (e.g., etoposide, taxol, digoxin, and vinblastine). Notably, these drugs are currently isolated from native plants grown in the field or in plant cell culture; identifying their biosynthetic enzymes would allow us to produce them more efficiently, engineer unnatural derivatives with improved properties, and even optimize the nutrient load in edible plants. The process of identifying plant metabolic enzymes has classically been slow and painstaking. Our approach is to merge transcriptomics, metabolomics, and synthetic biology to rapidly identify sets of enzymes that can be used to engineer an alternative host for production of specific plant molecules. Key publications and projects:
- Lau, W. and Sattely, E. S. “Six genes that complete biosynthetic pathway to the etoposide aglycone in Mayapple” Science, Vol. 349, No. 6253, pp. 1224-1228, 2015.
- Klein, A. P and Sattely, E. S. “Two Cytochromes P450 Catalyze S-Heterocyclizations in Cabbage Phytoalexin Biosynthesis” Nature Chem. Biol., Vol. 11, No. 11, pp. 837-839, 2015.
- NIH Genomes to Natural Products Initiative https://gnpn-genome.org
(2) Discovery and engineering of metabolic pathways for enhancing plant fitness. Plants thrive in the face of virtually every environmental stress: low nutrient input, pathogen attack, drought, and high salinity. However, agricultural crops have been bred for yield and food quality, and often lack fitness-promoting traits common in wild plants. As a result, farming these crops requires enormous energy inputs in the form of fertilizer and water, >20% of crops grown each year are lost to disease (Food Security 2012, 4, 519), and just 1/3 of the world’s land mass is considered arable. Among the many proposals for how to feed our growing population, there is broad agreement that improving plant fitness under non-ideal growth conditions is critical. The key to achieving this goal is to identify specific mechanisms that confer fitness and are practical engineering targets. Our approach is to focus on identifying metabolic pathways that enable plants to combat pathogens, acquire nutrients, or associate with beneficial microbes. The pathways are then the starting point for using metabolic engineering approaches to enhance plant fitness. Key publications:
- Klein, A. P.; Anarat-Cappillino, G.; Sattely, E. S. “Minimum Set of Cytochromes P450 for Reconstituting the Biosynthesis of Camalexin, a Major Arabidopsis Antibiotic” Angew. Chem. Int. Ed. Engl., Vol. 52, No. 51, 13625-13628, 2013.
- Rajniak, J; Barco, B.; Clay, N. K.; Sattely, E. S. “A New Cyanogenic Metabolite in Arabidopsis Required for Inducible Pathogen Defense” Nature, Vol. 525, No. 7569, pp. 276-279, 2015.
(3) Valorizing carbon in lignocellulosic biomass. Lignocellulose is the most abundant biopolymer on the planet and its utilization is a promising approach to building a short-circuit carbon cycle that bypasses fossil fuels. The majority of metabolic engineering efforts to date begin with glucose, and cellulose is an ideal source for this feedstock. However, the lignin content of lignocellulose (20-30% of total) represents a main challenge in harnessing this polymer’s carbon. First, it is recalcitrant and difficult to remove; second, there are no cost-effective ways to use the carbon stored in lignin. Notably, fungi and bacteria that grow on woody biomass efficiently convert lignin into soluble aromatics that resemble platform chemicals and then metabolize these monomers as a carbon source. Our goal is to engineer whole cell biocatalysts using enzymes from these microorganisms that liberate aromatic monomers from lignin to support the viability of lignocellulose as an energy feedstock. Key publications:
- Chung, Y-L.; Olsson, J. V.; Li, R. J.; Frank, C. W.; Waymouth, R. M.; Billington, S.; Sattely, E. S. “A Renewable Lignin-PLA Copolymer and Application in Biobased Composites,” 2013 ACS Sus. Chem. and Eng. Vol. 1, No. 10, 1231-1238, 2013.
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