Shiou-Chuan "Sheryl" Tsai
Assistant Professor, Molecular Biology and Biochemistry
Charlie Dunlop School of Biological Sciences
Charlie Dunlop School of Biological Sciences
Assistant Adjunct Professor, Chemistry
School of Physical Sciences
School of Physical Sciences
Ph.D., University of California, Berkeley, 1999, Chemistry
University of California, Irvine
2218 Natural Sciences 1
Mail Code: 3900
Irvine, CA 92697
2218 Natural Sciences 1
Mail Code: 3900
Irvine, CA 92697
Research Interests
Biochemistry. Biophysics. Bioorganic Chemistry. Structural Biology. Metabolic Engineering. Bioinformatics.
Websites
Appointments
1999-2003, Stanford University
Research Abstract
The Tsai lab studies the metabolic pathway and biosynthesis of natural products with high pharmaceutical impact, such as polyketides and sugars. Nature has a unique approach to generate a huge variety of natural products in a combinatorial fashion. Our goal is to understand and utilize nature’s approach to synthesize libraries of natural product analogs. Techniques utilized include organic synthesis, combinatorial biosynthesis, enzymology, bioinformatics and X-ray crystallography. The elucidation of molecular features that govern polyketide and sugar biosynthesis will help us understand how natural products are made and evolved in nature, and will enable rational design of "de novo" natural products for novel drug discovery.
Acyl-CoA Carboxylase: The Gatekeeper Enzyme
Acyl-coenzyme A carboxylases (ACC), such as acetyl-CoA carboxylase (AceCC) or propanyl-CoA carboxylase (PCC), catalyze the carboxylation of acetyl- and propanyl-CoA to provide malonyl- and methylmalonyl-CoA. This carboxylation reaction is one of the most important metabolic regulation checkpoints by committing acyl-CoA to the biosynthesis of fatty acids and polyketides. ACC and PCC are therefore targeted for therapeutics against obesity and diabetes, as well as herbicides and antibiotics. ACC and PCC in Streptomyces ceolicolor are 1 MDa multienzyme complexes containing at least 18 polypeptide chains. Structural and biochemical studies should shed light on the molecular basis of substrate recognition and the nature of the assembly. The multi-subunit structure also helps visualize different oligomeric architectures of ACC from different organisms, as well as the identification of future drug design targets.
Polyketide Biosynthesis
Polyketides, a large family of complicated and structurally diverse natural products (> 7000 compounds identified), are an extremely rich source of bioactive molecules. In the year 2001, 20% of top-selling drugs are polyketide-related products, illustrating the high impact of polyketides on pharmaceutical industry. Polyketides have therefore been intensely persued as total synthesis targets. In nature however, polyektides are made by polyketide synthase (PKSs), a multi-domain enzyme cluster that catalyzes repeated chain elongations and chain modifications. As nature’s total synthesis machinery, in vivo, PKS can synthesize kilogram quantity of polyketide natural products overnight. By combining different PKS domains, nature generates a large variation of polyketide natural products via a controlled variation in chain length, choice of chain-building units and optional chain modification. In light of nature’s strategy, we can perform total synthesis in a different approach. Novel "unnatural" polyketides can be synthesized by genetic engineering of PKS domains via addition, deletion, or rearrangment of individual domains, as well as by in vivo feeding of synthetic precursors. In addition to the chemical approach, a detailed biochemical study of PKS will help us to re-design both substrates and enzymes of PKS for novel drug discovery. A detailed understanding of the architecture, catalysis, and recognition properties of these remarkable multi-enzyme complexes will also help reveal how nature achieves its diversity in natural product biosynthesis.
Deoxysugar Biosynthesis
Deoxysugars are a distinct class of carbohydrates that has at least one hydroxyl group replaced with non-O-linked functional group. These sugars have a vital role in cellular adhesion and cell target recognition. No structure is available for enzymes that are involved in deoxysugar biosynthesis. Many deoxysugars are attached to polyketide natural products and are indispensible for the pharmaceutical activity. With the hope of expanding the substrate specificity of sugar-making enzymes, novel glycosylated compounds will be generated via redesign of deoxysugar biosynthesis enzymes. This can then be coupled with engineered polyketide biosynthesis to offer even greater variety of "unnatural" natural products.
Acyl-CoA Carboxylase: The Gatekeeper Enzyme
Acyl-coenzyme A carboxylases (ACC), such as acetyl-CoA carboxylase (AceCC) or propanyl-CoA carboxylase (PCC), catalyze the carboxylation of acetyl- and propanyl-CoA to provide malonyl- and methylmalonyl-CoA. This carboxylation reaction is one of the most important metabolic regulation checkpoints by committing acyl-CoA to the biosynthesis of fatty acids and polyketides. ACC and PCC are therefore targeted for therapeutics against obesity and diabetes, as well as herbicides and antibiotics. ACC and PCC in Streptomyces ceolicolor are 1 MDa multienzyme complexes containing at least 18 polypeptide chains. Structural and biochemical studies should shed light on the molecular basis of substrate recognition and the nature of the assembly. The multi-subunit structure also helps visualize different oligomeric architectures of ACC from different organisms, as well as the identification of future drug design targets.
Polyketide Biosynthesis
Polyketides, a large family of complicated and structurally diverse natural products (> 7000 compounds identified), are an extremely rich source of bioactive molecules. In the year 2001, 20% of top-selling drugs are polyketide-related products, illustrating the high impact of polyketides on pharmaceutical industry. Polyketides have therefore been intensely persued as total synthesis targets. In nature however, polyektides are made by polyketide synthase (PKSs), a multi-domain enzyme cluster that catalyzes repeated chain elongations and chain modifications. As nature’s total synthesis machinery, in vivo, PKS can synthesize kilogram quantity of polyketide natural products overnight. By combining different PKS domains, nature generates a large variation of polyketide natural products via a controlled variation in chain length, choice of chain-building units and optional chain modification. In light of nature’s strategy, we can perform total synthesis in a different approach. Novel "unnatural" polyketides can be synthesized by genetic engineering of PKS domains via addition, deletion, or rearrangment of individual domains, as well as by in vivo feeding of synthetic precursors. In addition to the chemical approach, a detailed biochemical study of PKS will help us to re-design both substrates and enzymes of PKS for novel drug discovery. A detailed understanding of the architecture, catalysis, and recognition properties of these remarkable multi-enzyme complexes will also help reveal how nature achieves its diversity in natural product biosynthesis.
Deoxysugar Biosynthesis
Deoxysugars are a distinct class of carbohydrates that has at least one hydroxyl group replaced with non-O-linked functional group. These sugars have a vital role in cellular adhesion and cell target recognition. No structure is available for enzymes that are involved in deoxysugar biosynthesis. Many deoxysugars are attached to polyketide natural products and are indispensible for the pharmaceutical activity. With the hope of expanding the substrate specificity of sugar-making enzymes, novel glycosylated compounds will be generated via redesign of deoxysugar biosynthesis enzymes. This can then be coupled with engineered polyketide biosynthesis to offer even greater variety of "unnatural" natural products.
Publications
1 Tsai, S. C.; Miercke, L. J.; Krucinski, J.; Chen, J. C. -H.; Foster, P. Gokhale, R.; Cane, D. E.; Khosla, C.; Stroud, R. M.; "Crystal Structure of the Macrocycle-Forming Thioesterase of the Erythromycin Polyketide Synthase: Versatility from a Unique Substrate Channel". PNAS, 2001, 98, 14808.
2 Lu, H.; Tsai, S. C.; Khosla, C.; Cane, D. E.; "Expression, Site-Directed Mutagenesis, and Steady State Kinetic Analysis of the Terminal Thioesterase Domain of the Methymycin/Picromycin Polyketide Synthase". Biochemistry, 2002, 41, 12590.
3 Tsai, S. C.; Lu, H.; Cane, D. E.; Khosla, C.; Stroud, R. M.; "Insights into Channel Architecture and Substrate Specificity from Crystal Structures of Two Macrocycle Forming Thioesterases of Modular Polyketide Synthases". Biochemistry, 2002, 41, 12598.
4 Pan, H.; Tsai, S. C.; Meadows, E.; Keatinge-Clay, A. T.; Miercke, L. J.; Stroud, R.; Khosla, C.; "Crystal Structure of the Priming Ketosynthase from the R1128 Biosynthetic Pathway: Implications for the Design of Novel Estrogen Receptor Antagonists". Structure, 2002, 10, 1559.
5 Keatinge-Clay, A. T.; Shelat, A. A.; Akahaven, D.; Tsai, S. C.; Miercke, L. J.; O’Connell, J.; Khosla, C.; Stroud, R. M.; "Catalysis, Specificity and ACP Docking Site of Streptomyces coelicolor Malonyl-CoA:ACP Transacylase". Structure, 2003, 11, 147.
2 Lu, H.; Tsai, S. C.; Khosla, C.; Cane, D. E.; "Expression, Site-Directed Mutagenesis, and Steady State Kinetic Analysis of the Terminal Thioesterase Domain of the Methymycin/Picromycin Polyketide Synthase". Biochemistry, 2002, 41, 12590.
3 Tsai, S. C.; Lu, H.; Cane, D. E.; Khosla, C.; Stroud, R. M.; "Insights into Channel Architecture and Substrate Specificity from Crystal Structures of Two Macrocycle Forming Thioesterases of Modular Polyketide Synthases". Biochemistry, 2002, 41, 12598.
4 Pan, H.; Tsai, S. C.; Meadows, E.; Keatinge-Clay, A. T.; Miercke, L. J.; Stroud, R.; Khosla, C.; "Crystal Structure of the Priming Ketosynthase from the R1128 Biosynthetic Pathway: Implications for the Design of Novel Estrogen Receptor Antagonists". Structure, 2002, 10, 1559.
5 Keatinge-Clay, A. T.; Shelat, A. A.; Akahaven, D.; Tsai, S. C.; Miercke, L. J.; O’Connell, J.; Khosla, C.; Stroud, R. M.; "Catalysis, Specificity and ACP Docking Site of Streptomyces coelicolor Malonyl-CoA:ACP Transacylase". Structure, 2003, 11, 147.
Professional Societies
Association of American Advanced Science
American Chemical Society
Protein Society
American Crystallographer Association
Graduate Programs
Protein Engineering
Structural Biology and Molecular Biophysics
Link to this profile
https://faculty.uci.edu/profile/?facultyId=4942
https://faculty.uci.edu/profile/?facultyId=4942
Last updated
07/28/2003
07/28/2003