 Professor of Pharmaceutical Science and Chemistry
Charles M. Johnson Chair in Pharmacy
B.Sc. 1982, Hangzhou University, China
M.S., 1984, The Chinese Academy of Sciences
Ph.D., 1991, Oregon State University
Room: 6109 Rennenbohm
Phone: 6080-263-2673
Email: bshen@pharmacy.wisc.edu
Position: Professor
Galm, U.; Wendt-Pienkowski, E.; Wang, L.; George, N.P.; Oh, T.-J.; Yi, F.; Tao, M.; Coughlin, J.M; Shen, B. (2009) The biosynthetic gene cluster of zorbamycin, a member of the bleomycin family of antitumor antibiotics, from Streptomyces flavoviridis ATCC21892. Mol. BioSyst. 4:77-90.
Beerman, T.A.; Gawron, L.S.; Shin, S.; Shen, B.; McHugh, M.M. (2009) C-1027, a radiomimetic enediyne anticancer drug, preferentially target hypoxic cells. Cancer Res. 69:593-598. Feng, Z,; Wang, L.; Rajski, S.R.; Xu, Z.; Coeffet-LeGal, M,F.; Shen, B. (2009) Engineered production of iso-migrastatin in heterologous hosts. Bioorg. Med. Chem. 17:2147-2159. Ju, J.; Rajski, S.R.; Lim, S.-K.; Seo, J.-W.; Peters, N.R.; Hoffmann, F.M.; Shen, B. (2009) Lactimidomycin, iso-migrastatin and related glutarimide-containing 12-membered macrolides are extremely potent inhibitors of cell migration. J. Am. Chem. Soc. 131:1370-1371. Lin, S.; Van Lanen, S.G.; Shen, B. (2009) A free-standing condensation enzyme catalyzing ester bond formation in C-1027 biosynthesis. Proc. Natl. Acad. Sci. U.S.A. 106:4183-4188. Rajski, S.R.; Shen, B. (2009) The role of evolution in the discovery of new drugs and chemicals. In ACS Symposium Series: Chemical Evolution II: From Origins of Life to Modern Society, Zaikowski, L.; Friedrich, J.M.; Seidel, S.R. Eds., ACS, Washington DC, in press. Horsman, G.P.; Van Lanen, S.G.; Shen, B. (2009) Iterative type I polyketide synthase for enediyne core biosynthesis. Methods in Enzymology 459:97-112.
Jiang, H.; Rajski, S. R.; Shen, B. (2009) Tandem acyl carrier protein domains in polyunsaturated fatty acid synthases. Methods in Enzymology 459:79-96. Cheng, Y.-Q.; Coughlin, J.M.; Lim, S.-K.; Shen, B. (2009) Type I polyketide synthases that require discrete acyltransferases. Methods in Enzymology 459:165-186. Smanski, M.J.; Peterson, R.M.; Rajski, S.R.; Shen, B. (2009) Engineered Streptomyces platensis strains that overproduce antibiotics platensimycin and platencin. Antimicrob. Agents Chermother. 53:1299-1304. Li, W.; Luo, Y.; Ju, J.; Rajski, S.R. ; Osada, H. ; Shen, B. (2009) Characterization of the tautomycetin biosynthetic gene cluster from Streptomyces griseochromogenes provides new insight into dialkylmaleic anhydride biosynthesis. J. Nat. Prod. 72:450-459. Liao, R.; Duan, L.; Lei, C.; Pan, H.; Ding, Y.; Zhang, Q.; Chen, D.; Shen, B.; Yu, Y.; Liu, W. (2009) Thiopeptide biosynthesis featuring ribosomally synthesized precursor peptides and conserved posttranslational modifications. Chem. Biol. 16:141-147. Wang, L.; Tao, M.; Wendt-Pienkowski, E.; Galm, U.; Coughlin, J.M.; Shen, B. (2009) Functional characterization of tlmK unveiling unstable carbinolamide intermediates in the tallysomycin biosynthetic pathway. J. Biol. Chem. 284:8256-8264. Huang, S.-X.; Zhao, L.-X.; Tang, S.-K.; Jiang, C.-L.; Duan, Y.; Shen, B. (2009) Erythronolides H and I, new erythromycin congeners from a halophilic actinomycete Actinopolyspora sp. YIM90600. Org. Lett. 11:1353-1356. Ju, J.; Li, W.; Yuan, Q.; Peters, N. ; Hoffmann, F.M., Rajski, S.R.; Osada, H.; Shen, B. (2009) Functional characterization of ttmM unveils new tautomycin analogs and insight into tautomycin biosynthesis and activity. Org. Lett. 11:1639-1642. Adler, J.; Cook, M.; Luo, Y.; Pitt, S.; Ju, J.; Li, W.; Shen, B.; Kunnimalaiyaan, M.; Chen, H. (2009) Tautomycetin and tautomycin suppress the growth of medullary thyroid cancer cells via inhibition of GSK-3ß. Mol. Cancer Therap. 8:914-920. Liu, T.; Huang, Y.; Shen, B. (2009) The bifunctional acyltransferase/decarboxylase LnmK as the missing link for b-alkylation in polyketide biosynthesis. J. Am. Chem. Soc. 131:6900-6901. Pinchot, S. N.; Adler, J. T.; Luo, Y.; Ju, J.; Li, W.; Shen, B.; Kunnimalaiyaan, M.; Chen, H. (2009) Tautomycin suppress the growth and neuroendocrine hormone markers in carcinoid cells through activation of the raf-1 pathway. Am. J. Surg. 197:313-319. Chen, Y.; Wendt-Pienkowski, E.; Rajski, S. R.; Shen, B. (2009) In vivo investigation of the roles of FdmM and FdmM1 in fredericamycin biosynthesis unveiling a new family of oxygenases. J. Biol. Chem. 284:24735-24743.
| Research Description
Microorganisms produce a large variety of biologically active substances representing a vast diversity of fascinating molecular architecture not available in any other systems. Our research centers on the chemistry, biochemistry and genetics of the biosynthesis of these secondary metabolites. Blending organic chemistry, biochemistry, and molecular biology, we take a multidisciplinary approach to study the secondary metabolism by asking the following questions: what reactions are available in nature, what are the enzymatic mechanisms of these reactions, how are these reactions linked to produce complex structures, what are the regulatory mechanisms of these pathways, and, ultimately, how can we manipulate nature's biosynthetic machinery for the discovery and development of new drugs. Members of our group gain broad training spanning organic chemistry, biochemistry, microbiology and molecular biology, a qualification that is becoming essential for the modern bioorganic chemists and chemical biologists who seek career opportunity in both academia and pharmaceutical and biotechnology industry.
Current research projects
(1) Cloning and characterization of novel natural product biosynthetic gene clusters and machinery: We continue to develop new strategies to clone and characterize natural product biosynthetic gene clusters from actinomycetes. Current targets include (i) anticancer antibiotics bleomycin, C-1027, dorrigocins, fredericamycin, lectimidomycin, leinamycin, maduropeptin, migrastatin, neocarzinostatin, tallysomycin, tautomycetin, tautomycin, telomestatin, and zorbamycin, (ii) antibacterial antibiotics oxazolomycin, platencin, and platensimycin, and (iii) macrotetrolides and paramycin.
(2) Discovery and elucidation of novel enzymes, biochemistry, and mechanism of catalysis: From the 20 natural product biosynthetic gene clusters we have cloned and characterized over the past decade, we have uncovered more than 500 novel proteins! Current effort on characterizing these novel enzymes has been focused on (i) polyketide synthases (PKSs), (ii) nonribosomal peptide synthetases (NRPSs), (iii) hybrid PKS-NRPS, (iv) terpene synthases of microbial origin, (v) MIO-containing aminomutases, (vi) enzymes acting on carrier protein-tethered substrates, and (vii) novel oxidoreductases.
(3) Engineering of natural product structure diversity by combinatorial biosynthesis methods for drug discovery and development: Natural products remain the best sources of drugs and drug leads, but a natural product-based drug discovery and development program is often hampered by (i) the complex molecular architecture of natural products that renders chemical total synthesis and medicinal chemistry ineffective, limiting their accessibility for both mechanistic and clinical studies, (ii) the unknown or poorly characterized molecular targets, and (iii) the general dose-limiting toxicity due to lack of target specificity. We have carefully selected a set of promising natural product leads of microbial origin and are developing them into clinically useful drugs via enhancing structural diversity, identifying novel targets, and delivering the natural product drugs to specific cancer cells by combinatorial biosynthesis approaches. The resultant libraries are evaluated by in vitro and in vivo methods and promising leads are being further developed through preclinical studies.
(4) Expression of natural product biosynthetic gene clusters in heterologous hosts for natural product production and engineering: Natural products are in high demand as therapeutics, building blocks, and biochemical tools yet are often produced in miniscule amounts and as components of complex mixtures by their producing organisms. The structural complexity of such compounds poses a tremendous challenge to production by benchtop synthesis making large-scale fermentation of the producing microbe the most effective means of large-scale manufacture. Still, production by fermentation is often a lengthy, empirical and frustrating process. We are developing a suite of microorganisms that can enable the convenient, high-yield production and engineering of a wide range of natural products from actinomycetes, one of the most prolific producers of biologically active natural products.
5) Microbial natural product isolation and structural elucidation for anticancer and antiinfective drug discovery: We are isolating novel natural products from under-explored microorganisms, including (i) endophytes, (ii) actinomycetes, and (iii) extremophiles. The criteria for strain selection are (i) the uniqueness and richness of biodiversity, (ii) symbiosis with traditional Chinese medicinal plants, (iii) morphological and taxonomical distinctiveness, and (iv) bias towards actinomycetes. We are (i) optimizing natural product production, (ii) preparing extracts for high-throughput (HTP) screening and LC-MS dereprelication, (iii) isolating and determining the structures of the novel natural products, and (iv) identifying novel natural products as leads for drug discovery.
Last updated February 20, 2008.
Charles M. Johnson Chair in Pharmacy, School of Pharmacy, UW-Madison, WI, 2004- Jack L. Beal Award, American Society of Pharmacognosy, 2002 Independent Scientist Award, NIH, 2001-06 Matt Suffness Award, American Society of Pharmacognosy, 2000 CAREER Award, NSF, 1998-03 Searle Scholar, Searle Scholars Program/Chicago Community Trust, 1997-00 FIRST Award, NIH, 1996-01
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