Biochemistry, Chemical Biology, Structural Biology, Enzymology, Microbiology
Pew Scholar, 2006
School of Biological Sciences Golden Apple Award in Teaching Excellence, 2007
School of Biological Sciences Teaching Excellence Award, the Division of Undergraduate Education, 2009
Outstanding Professor from UC Irvine School of Biological Sciences, selected by the graduating seniors, 2010
UCI Chancellor's Fellow, 2011
UCI Chancellor's Award for Excellence in Undergraduate Research, 2013
Fellow of the Royal Society of Chemistry (FRSC), 2014
AAAS Fellow, 2016
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.
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.
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.
Structural basis for acyl-CoA carboxylase-mediated assembly of unusual polyketide synthase extender units incorporated into the stambomycin antibiotics
Lauren Ray, Timothy Valentic, Takeshi Miyazawa, David M. Withall, Lijiang Song, Hiroyuki Osada,Shunji Takahashi,Shiou-Chuan Tsai,* and Gregory L. Challis*
(* Co-corresponding authors)
Nature Comm., 2016, in press
Comprehensive Analysis of a Novel Ketoreductase for Pentangular Polyphenol Biosynthesis
Valentic TR, Jackson DR, Brady SF, Tsai SC.
ACS Chem Bio. 2016, in press
Structural and Biochemical Analysis of Protein-Protein Interactions Between the Acyl-Carrier Protein and Product Template Domain.
Barajas JF, Finzel K, Valentic TR, Shakya G, Gamarra N, Martinez D, Meier JL, Vagstad AL, Newman AG, Townsend CA, Burkart MD, Tsai SC
Angew Chem Int Ed Engl. 2016, in press
Insights into complex oxidation during BE-7585A biosynthesis: structural determination and analysis of the polyketide monooxygenase BexE.
Jackson DR, Yu X, Wang G, Patel AB, Barajas JF, Sasaki E, Metsa-Ketala M, Liu HW, Rohr J, Tsai SC.
ACS Chem Biol. 2016, 11, 1137
The alga Ochromonas danica produces bromosulfolipids.
White AR, Duggan BM, Tsai SC, Vanderwal CD
Org Lett. 2016, 18, 1124
Structural insights into anthranilate priming during type II polyketide biosynthesis.
Jackson D, Tu SS, Nguyen M, Barajas J, Schaub A, Krug D, Pistorius D, Luo R, Müller R, Tsai SC.
ACS Chem Biol. 2016, 11, 95
An unusual intramolecular trans-amidation.
Rivera H Jr, Dhar S, La Clair JJ, Tsai SC#, Burkart MD#
Tetrahedron. 2016, 72, 3605
Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases.
Caldara-Festin G, Jackson DR, Barajas JF, Valentic TR, Patel AB, Aguilar S, Nguyen M, Vo M, Khanna A, Sasaki E, Liu H, Tsai SC.
Proc Natl Acad Sci U S A. 2015, 112, E6844-51
Probing the substrate specificity and protein-protein interactions of the E. coli fatty acid dehydratase, FabA.
Finzel K, Nguyen C, Jackson DR, Gupta A, Tsai SC#, Burkart MD#
Chem Biol. 2015, 22, 1453
Comprehensive structural and biochemical analysis of the terminal myxalamid reductase domain for the engineered production of primary alcohols.
Barajas JF, Phelan RM, Schaub AJ, Kliewer JT, Kelly PJ, Jackson DR, Luo R, Keasling JD, Tsai SC.
Chem Biol. 2015, 22, 1018
Trapping the dynamic acyl carrier protein in fatty acid biosynthesis.
Nguyen C, Haushalter RW, Lee DJ, Markwick PR, Bruegger J, Caldara-Festin G, Finzel K, Jackson DR, Ishikawa F, O'Dowd B, McCammon JA, Opella SJ, #Tsai SC, #Burkart MD.
Nature. 2014, 505, 427
# Corresponding authors.
Editorial: fungal natural products themed issue.
Challis GL, Tsai SC.
Nat Prod Rep. 2014, 31, 1241
Modeling linear and cyclic PKS intermediates through atom replacement
Shakya G, Rivera H Jr, Lee DJ, Jaremko MJ, La Clair JJ, Fox DT, Haushalter RW, Schaub AJ, Bruegger J, Barajas JF, White AR, Kaur P, Gwozdziowski ER, Wong F, Tsai SC#, Burkart MD#
J Am Chem Soc. 2014, 136, 16792
Polyketide synthase: sequence, structure, and function
Bruegger J, Caldara G, Beld J, Burkart MD, Tsai SC.
Natural Products: Discourse, Diversity, and Design, 2014, 219
The determinants of activity and specificity in actinorhodin type II polyketide ketoreductase.
Javidpour P, Bruegger J, Srithahan S, Korman TP, Crump MP, Crosby J, Burkart MD, Tsai SC.
Chem Biol. 2013, 20, 1225
Probing the selectivity and protein·protein interactions of a nonreducing fungal polyketide synthase using mechanism-based crosslinkers.
Bruegger J, Haushalter B, Vagstad A, Shakya G, Mih N, Townsend CA, Burkart MD, Tsai SC.
Chem Biol. 2013, 20, 1135
Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis.
Ames BD, Nguyen C, Bruegger J, Smith P, Xu W, Ma S, Wong E, Wong S, Xie X, Li JW, Vederas JC, Tang Y, Tsai SC.
Proc Natl Acad Sci U S A. 2012, 109, 11144
"Insight into the molecular basis of aromatic polyketide cyclization: crystal structure and in vitro characterization of WhiE-ORFVI." Lee MY, Ames BD, Tsai SC.
Biochemistry, 2012, 51, 3079
"Structural enzymology of polyketide synthases", Ames BD, Tsai SC.
Methods Enzymol. 2009, 459, 17.
Babysitting flavin for biosynthesis.
Chem Biol. 2012, 19, 787
"Structural and biochemical analyses of regio- and stereospecificities observed in a type II polyketide ketoreductase" Javidpour P, Korman TP, Shakya G, Tsai SC
Biochemistry. 2011, 50, 4638.
"Structural and biochemical characterization of ZhuI aromatase/cyclase from the R1128 polyketide pathway" Ames BD, Lee MY, Moody CL, Zhang W, Tang Y, Tsai SC
Biochemistry, 2011, 50, 8392.
"Structural and biochemical studies of the hedamycin type II polyketide ketoreductase (HedKR): molecular basis of stereo- and regiospecificities" Javidpour P, Das A, Khosla C, Tsai SC
Biochemistry, 2011, 50, 7426.
"Fatty acid biosynthesis in actinomycetes" Gago G, Diacovich L, Arabolaza A, Tsai SC, Gramajo H
FEMS Microbiol Rev. 2011, 35, 475.
"Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis" Korman TP*, Crawford JM*, Labonte JW, Vagstad AL, Wong J, Townsend CA#, and Tsai SC#
# Corresponding authors.
Proc. Natl. Acad. Sci. USA. 2010, 107, 6246.
"Crystal structures and mutational analyses of acyl-CoA carboxylase beta subunit of Streptomyces coelicolor" Arabolaza A*, Shillito ME*, Lin TY, Diacovich L, Melgar M, Pham H, Amick D, Gramajo H, and Tsai SC
Biochemistry, 2010, 49, 7367.
"X-ray crystallographic structure of an artificial beta-sheet dimer" Khakshoor O, Lin AJ, Korman, TP, Sawaya MR, Tsai SC, Eisenberg D, Nowick JS
J. Am. Chem. Soc. 2010, 132, 33.
"2.6 Å X-ray crystal structure of human p53R2, a p53 inducible ribonucleotide reductase" Smith P*, Zhou, BZ*, Ho N, Yuan YC, Su L, Tsai SC#, Yen Y#.
* Contributing equally.
# Corresponding authors.
Biochemistry, 2009, 48, 11134.
"Accase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria", Kurth DG, Gago GM, de la Iglesia A, Bazet Lyonnet B, Lin TW, Morbidoni HR, Tsai SC, Gramajo H
Microbiology, 2009, 155, 2664.
"Influence relevance voting: an accurate and interpretable virtual high throughput screening method", Swamidass SJ, Azencott CA, Lin TW, Gramajo H, Tsai SC, Baldi P
J Chem Inf Model. 2009, 49, 756.
"Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization" Crawford JM, Korman TP, Labonte JW, Vagstad AL, Hill EA, Kamari-Bidkorpeh O, Tsai SC#, and Townsend CA#
# Corresponding authors.
Nature, 2009, 461, 1139.
"Structural enzymology of type II polyketide synthase: the structure-sequence-function correlation" Korman TP, Ames BD, Tsai SC. in "Comprehensive Natural Products", 2009, Elsevier Press.
"Inhibition Kinetics and Emodin Cocrystal Structure of a Type II Polyketide Ketoreductase." Korman TP, Tan YH, Wong J, Luo R, Tsai SC.
Biochemistry. 2008, 47, 1837
"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, 47, 6329
“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.
"The type I fatty acid and polyketide synthases: a tale of two megasynthases." Smith S, Tsai SC.
Nat Prod Rep. 2007, 24, 1041
"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.
"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, 188, 477
"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.
"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
"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.
"Structural analysis of actinorhodin polyketide ketoreductase: cofactor binding and substrate specificity." Korman TP, Hill JA, Vu TN, Tsai SC.
Biochemistry 2004, 43, 14529
"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, 43, 14027
"A fine balancing act of type III polyketide synthase." Tsai SC
Chem Biol. 2004, 11, 1177
American Chemical Society
American Crystallographer Association
American Association of Advanced Science
Structural Biology and Molecular Biophysics
Cellular and Molecular Biosciences
Medicinal Chemistry and Pharmacology
Chao Family Comprehensive Cancer Center (UCI)
Institute for Genomics and Bioinformatics (UCI)
Center of Structural and Chemical Biology (UCI)