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"Metabolic Engineering for Understanding and Harnessing Nature’s Biosynthetic Potential” -Sijin Li
Friday, October 18, 2019 at 12:20pm
Plant Science Building, 404
Assistant Professor,Smith School of Chemical and Biomolecular Engineering
Plant natural products are chemicals of great pharmaceutical significance due to their structural complexity and chemical diversity. However, discovery and manufacturing of plant natural products have lagged behind those of microbial natural products primarily due to the size and complexity of plant genomes and the difficulty in plant biosynthetic pathway prediction and engineering. Our research goal is to develop metabolic engineering and synthetic biology platforms that enable the systematic discovery and production of plant natural products and their derivatives, ultimately transforming our ability to understand how nature achieves complex compound biosynthesis.
Metabolic engineering platforms for plant natural product biosynthesis and engineering
- Microbial synthesis of high-value phytochemicals, Nature Chemistry, 2018, 10, 395-404
- Complete and engineered biosynthesis of noscapine in yeast, Proceedings of the National Academy of Sciences, 2018, 115.17, 3922-3931
A yeast-based plant natural product manufacturing process has the potential to address many problems in current plant-based supply chains, as industrial cultivation of yeast is not susceptible to environmental factors in plant farming process, and also provides greater product consistency and higher production rate. Since chemical diversity is critical for drug candidate preparation in pharmaceutical synthesis, the biosynthesis process in yeast also offers a versatile platform to produce various natural product derivatives. Traditional chemical synthesis of NP derivatives may suffer from the lack of available synthetic intermediates, while yeast-based biosynthesis can provide previously inaccessible intermediates and enable functional group interconversion and addition (e.g., acylation, alkylation, and halogenation) via enzymatic conversion.
We use synthetic biology and metabolic engineering approaches for scalable plant natural product biosynthesis and engineering. We are developing a transformative platform specifically tailored for complex plant natural product synthesis and modification in yeast. For efficient pathway reconstruction in yeast, synthetic biology toolkits and pathway assembly paradigms enable the heterologous assembly and expression of plant pathways in yeast. Further optimization efforts including metabolic engineering, protein directed evolution, and fermentation optimization will further improve complex natural product manufacturing.
Bioinformatics-driven pipeline for novel plant natural product discovery
The vast majority of plant natural products remain unknown due to the lack of efficient discovery methods. Successful natural product discovery from bacteria and fungi by identifying microbial biosynthetic gene clusters arranged in operons offers a promising genomics-driven discovery strategy as an alternative to traditional bioactivity screening. However, discovery in plant via pathway prediction is more challenging, mainly due to (1) lack of plant pathway prediction approaches, (2) difficulty in large-scale gene manipulation in natural plant hosts, and (3) limited availability of plant genome sequences.
Our efforts in establishing an innovative discovery pipeline will accelerate plant natural product discovery within a yeast-based synthetic biology platform. The explosion of plant genomics and transcriptomics information lays the groundwork for systematic plant pathway prediction, as one gene identified to be involved in plant natural product biosynthesis can be used as a “bait” to extract other pathway genes from the functional genomics datasets. Meanwhile, with more synthetic biology tools and simpler metabolic background compared to model plants, yeast can serve as a versatile heterologous host for plant gene functional expression and multi-gene pathway reconstruction. Consequently, the integration of bioinformatics-driven pathway prediction and yeast engineering will lead to a discovery pipeline complementary to the plant-based discovery approach, support the future development of scalable drug manufacturing platforms, and ultimately advance plant natural product based drug discovery and development.