Shiou-Chuan (Sheryl) TsaiAssistant Professor, Molecular Biology & Biochemistry Assistant Professor, Chemistry |
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Research Interests |
Biochemistry, Chemical Biology, Structural Biology, Microbiology | |
| URLs | UCI Faculty Profile | |
| MB&B Faculty | ||
| Chemistry Faculty | ||
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Academic Distinctions |
Pew Scholar, 2006 School of Biological Sciences Golden Apple Award in Teaching Excellence, 2007 |
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Research Abstract |
Nature has a unique approach to generate a huge variety of natural products in a combinatorial fashion. These compounds include fatty acids, sugars and pharmaceutically important compounds such as polyketides. 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 these multi-domain complexes and to utilize natures approach of biosynthesis. 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, catalysis and dynamics of these enzyme complexes that have biological significance. Techniques utilized include organic synthesis, combinatorial biosynthesis, enzymology, bioinformatics and X-ray crystallography. The elucidation of molecular features that govern fatty acid, 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. AceCC and PCC are therefore targeted for therapeutics against obesity and diabetes, as well as herbicides and antibiotics. AceCC and PCC in Streptomyces ceolicolor 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, the nature of the assembly and how ACC is regulated. This in turn will lead to the identification of drug design candidates.  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 pursued as total synthesis targets. In nature however, polyeketides are made by polyketide synthase (PKSs), a multi-domain enzyme cluster that catalyzes repeated chain elongations and chain modifications. As natures 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 natures 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 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 a combinatorial fashion.  Proposed architecture of a multi-domain PKS fragment based on biophysical evidences. These catalytic domains can produce do novo natural products via combinatorial biosynthesis, in which catalytic domains are shuffled to offer products that are different (in red, representative examples) from the original template (in blue). 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.  . |
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| Publications |
"Structure and Mutagenic Retroevolution of E1 Dehydrase: at the Crossroads of Dehydration, Aminotransfer and Racemization", Smith P, Szu P, Bui C, Liu HW, Tsai SC. Biochemistry, 2008, in press. |
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Crystal Structure and Functional Analysis of Tetracenomycin ARO/CYC: Implications for Cyclization Specificity of Aromatic Polyketides. Ames BD, Korman TP, Zhang W, Smith P, Vu T, Tang Y, Tsai SC. Proc. Natl. Acad. Sci. USA. 2008, 105, 5349. |
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"Inhibition Kinetics and Emodin Cocrystal Structure of a Type II Polyketide Ketoreductase." Korman TP, Tan YH, Wong J, Luo R, Tsai SC. Biochemistry. 2008 Feb 19;47(7):1837-47. |
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"The type I fatty acid and polyketide synthases: a tale of two megasynthases." Smith S, Tsai SC. Nat Prod Rep. 2007 Oct;24(5):1041-72. |
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"Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis" Lin TW, Melgar MM, Kurth D, Swamidas SJ, Gago G, Purdon J, Tseng T, Baldi P, Gramajo H, Tsai SC Proc. Nat. Acad. Sci. 2006 103, 3072-7. |
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"Biosynthesis of a 3,6-dideoxyhexose: crystallization and X-ray diffraction of CDP-6-deoxy-threo-glycero-4-hexulose-3-dehydrase (E1) for ascarylose biosynthesis" Smith P, Lin A, Szu P.-h., Liu, H.-w., Tsai SC Acta Crystal. F 2006 62(Pt 3), 231-4. |
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"Engineered Biosynthesis of a Novel Amidated Polyketide Using the Malonamyl-specific Initiation Module from the Oxytetracycline Polyketide Synthase" Zhang W, Ames BD, Tsai SC, Tang Y Applied and Environmental Microbiology 2006, 72, 2573-80 |
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"Biochemical and structural characterization of an essential acyl coenzyme A carboxylase from Mycobacterium tuberculosis." Gago G, Kurth D, Diacovich L, Tsai SC, Gramajo H J Bacteriol. 2006 Jan;188(2):477-86. |
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| "Structural Enzymology of Aromatic Polyketide Synthase." Korman TP, Ames BD, Tsai, SC. In ACS Volume Based on Polyketides: Biosynthesis, Biological Activity and Genetic Engineering. eds S. R. Baerson; American Chemical Society, 2006. | ||
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"Structural analysis of actinorhodin polyketide ketoreductase: cofactor binding and substrate specificity." Korman TP, Hill JA, Vu TN, Tsai SC. Biochemistry. 2004 Nov 23;43(46):14529-38. |
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"Crystal structure of the beta-subunit of acyl-CoA carboxylase: structure-based engineering of substrate specificity." Diacovich L, Mitchell DL, Pham H, Gago G, Melgar MM, Khosla C, Gramajo H, Tsai SC. Biochemistry. 2004 Nov 9;43(44):14027-36. |
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"A fine balancing act of type III polyketide synthase." Tsai, S.C.. Chem Biol. 2004 Sep;11(9):1177-8. |
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Professional Societies |
American Chemical Society Protein Society American Crystallographer Association American Association of Advanced Science |
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| Graduate Programs |
Structural Biology and Molecular Biophysics Chemical Biology Molecular Biology, Genetics and Biochemistry Chemistry Biotechnology Medicinal Chemistry and Pharmacology |
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| Research Centers | Chao Family Comprehensive Cancer Center (UCI) | |
| Institute for Genomics and Bioinformatics (UCI) | ||
| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=4944 | |
| Last updated | 04/11/2008 | |
