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Shiou-Chuan (Sheryl) Tsai

Associate Professor, Molecular Biology and Biochemistry School of Biological Sciences Associate Professor, Chemistry School of Physical Sciences Associate Professor Pharmaceutical Sciences

B.S., National Taiwan University, 1990, Chemistry (Liu Lab) M.S., National Taiwan University, 1992, Chemistry (Liu Lab) Ph.D., University of California, Berkeley, 1999, Chemistry (Klinman Lab) Postdoctoral Researcher, Stanford University (Khosla Lab) and UCSF (Stroud Lab), 2003

Research Interests Biochemistry, Chemical Biology, Structural Biology, Microbiology

Faculty/lab web: http://www.faculty.uci.edu/profile.cfm?faculty_id=4944

Faculty/lab web: http://www.faculty.uci.edu/scripts/UCIFacultyProfiles/detailMBB.cfm?ID=4944

Faculty/lab web: http://www.chem.uci.edu/people/faculty/sctsai/

Graduate Programs: Structural Biology and Molecular Biophysics Chemical Biology Cellular and Molecular Biosciences Chemistry Biotechnology Medicinal Chemistry and Pharmacology

Professional Society American Chemical Society Protein Society American Crystallographer Association American Association of Advanced Science

Abstract Nature has a unique approach to generate a huge variety of natural products in a combinatorial fashion. The biosynthesis of these compounds is often accomplished by multi-domain enzyme mega-complexes with remarkable architectures. The goal of the Tsai lab is to understand the sequence-structure-function relationship of these multi-domain complexes, so that we may biosynthesize chemically complex natural products in an efficient fashion. Our research is highly inter-disciplinary: in terms of chemistry, our research leads to libraries of de novo natural product analogs in a combinatorial fashion with high yield and efficiency; in terms of biology, our research will help understand the architecture and catalysis of these enzyme complexes. Techniques utilized include organic synthesis, combinatorial biosynthesis, molecular cloning, enzymology, bioinformatics and X-ray crystallography. The elucidation of molecular features that govern natural product 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 drug discovery. Acyl-CoA Carboxylase: The Gatekeeper Enzyme Acyl-coenzyme A carboxylases (ACCase), such as acetyl-CoA carboxylase (ACC) or propionyl-CoA carboxylase (PCC), catalyze the carboxylation of acetyl- and propionyl-CoA to provide malonyl- and methylmalonyl-CoA, respectively. ACCase is a key metabolic enzyme that commits acyl-CoA to the biosynthesis of fatty acids and polyketides. ACC and PCC are targeted for therapeutics against obesity and diabetes, as well as herbicides and antibiotics. ACC and PCC in Actinomycetes are 1 MDa multi-domain enzyme 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 This in turn will lead to the identification of drug design candidates. The hexameric architecture of the beta-subunit of ACC, a highly-regulated enzyme complex that commits acyl-CoA to fatty acid and polyketide biosynthesis. Polyketide Biosynthesis Polyketides, a large family of complicated and structurally diverse natural products (> 10000 compounds identified), are an extremely rich source of bioactive molecules. The annual sales of polyketide-related drugs are more than $17 billions, illustrating the high impact of polyketides on pharmaceutical industry. Polyketides have been intensely pursued as total synthesis targets. In Nature, polyeketides are made by polyketide synthase (PKSs), a multi-domain enzyme cluster that catalyzes repeated chain elongations and chain modifications. 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. De novo polyketides can be synthesized by genetic engineering of PKS domains via domain rearrangement, as well as by in vivo feeding of synthetic precursors. In addition to the chemical approach, a detailed biochemical and structural study of PKS will help us to re-design both substrates and enzymes of PKS for 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 a combinatorial fashion. 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 indispensable 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 de novo natural products. Structural and biochemical studies will further help us understand the molecular mechanism and protein-protein interaction of these deoxysugar-producing enzymes.

Other Experience

Updated: Last Updated: 10/14/2009