Shen, Ben - The Scripps Research Institute

研究领域

Natural Product Biosynthesis, Engineering, and Drug Discovery. 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 who seek career opportunity in both academia and pharmaceutical and biotechnology industry (http://www.scripps.edu/shen/). The Natural Products Library Initiative (NPLI) at TSRI. Natural products are significantly underrepresented in current small molecule libraries. The current NPL at TSRI consists of: (i) purified natural products with fully assigned structures, (b) MPLC (on C-18 semipreparative column) fractions, and (c) crude extracts. The NPL is presented in 384-well format with all materials dissolved in DMSO (1 mM for pure compounds and 50 mg/mL for fractions and extracts), compatible with most of the HTS platforms. The NPL at TSRI currently available for screening includes: (a) 3,000 strains, (b) 450 pure natural products, (c) 1,500 MPLC fractions, and (d) 5,500 crude extracts. The NPL grows at the rate of 100 strains/month and crude extracts, MPLC fractions, and pure natural products derived thereof. The NPL provides an unprecedented molecular diversity to screen emerging targets for drug leads, and selected members of the NPL serves as outstanding small molecule probes to interrogate biology

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Coughlin, J. M.; Rudolf, J. D.; Wendt-Pienkowski, E.; Wang, L.; Unsin, C.; Galm, U.; Yang, D.; Tao, M.; Shen, B. (2014) BlmB and TlmB Provide Resistance to the Bleomycin Family of Antitumor Antibiotics by N-Acetylating Metal-Free Bleomycin, Tallysomycin, Phleomycin, and Zorbamycin. Biochemistry, 53, 6901–6909. [PubMed] Hindra; Huang, T.; Yang, D.; Rudolf, J. D.; Xie, P.; Xie, G.; Teng, Q.; Lohman, J. R.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Duan, Y.; Shen, B.(2014) Strain Prioritization for Natural Product Discovery by a High-Throughput Real-Time PCR Method. J. Nat. Prod., 77, 2296-2303. [PubMed] Ge, H.-M.; Huang, T.; Rudolf, J. D.; Lohman, J. R.; Huang, S.-X.; Guo, X.; Shen, B.(2014) Enediyne Polyketide Synthases Stereoselectively Reduce the Β-Ketoacyl Intermediates to Β- D-Hydroxyacyl Intermediates in Enediyne Core Biosynthesis. Org. Lett., 16: 3958–3961. [PubMed] Yin, M.; Yan, Y.; Lohman, J. R.; Huang, S.-X.; Ma, M.; Zhao, G.-R.; Xu, L.-H.; Xiang, W.; Shen, B. (2014) Cycloheximide and actiphenol production in Streptomyces sp. YIM56141 governed by single biosynthetic machinery featuring an acyltransferase-less type I polyketide synthase. Org. Lett. 16:3072-3075. [PubMed] Xie, P.; Ma, M.; Rateb, M. E.; Shaaban, K. A.; Yu, Z.; Huang, S.-X.; Zhao, L.-X.; Zhu, X.; Yan, Y.; Peterson, R. M.; Lohman, J. R.; Yang, D.; Yin, M.; Rudolf, J. D.; Jiang, Y.; Duan, Y.; Shen, B. (2014) Biosynthetic potential-based strain prioritization for natural product discovery - a showdase for diterpenoid producing actinomycetes. J. Nat. Prod. 77:377-387. [PubMed] Peterson, R. M.; Huang, T.; Rudolf, J. D.; Smanski, M. J.; Shen, B. (2014) Mechanisms of self-resistance in the platensimycin and platencin producing Streptomyces platensis MA7327 and MA7339 strains. Chem. Biol. 21:389-397. [PubMed] Lohman, J. R.; Ma, M.; Cuff, M. E.; Bigelow, L.; Bearden, J.; Babnigg, G.; Joachimiak, A.; Phillips Jr., G. N.; Sheb, B. (2014) The crystal structure of BlmI as a model for nonribosomal peptide synthetase peptidyl carrier proteins. Proteins, 82:1210-1218. Rateb, M. E.; Yu, Z.; Yan, Y.; Yang, D.; Huang, T.; Vodanovic-Jankovic, S.; Kron, M. A.; Shen, B. (2014) Medium optimization of Streptomyces sp. 17944 for tirandamycin B production and isolation and structural elucidation of tirandamycins H, I, and J. J. Antibiot. 67:127-132. [PubMed] Falzone, M.; Martens, E.; Tynan, H.; Maggio, C.; Golden, S.; Nayda, V.; Crespo, E.; Inamine, G.; Gelber, M.; Lemense, R.; Chiapinni, N.; Friedman, E.; Shen, B.; Gullo, V.; Demain, A. L. (2013) Development of a chemically-defined medium for the production of the antibiotic platensimycin by Streptomyces platensis. Appl. Microbiol. Biotechnol. 97:9535-9539. [PubMed] Horsman, G. P.; Lechner, A.; Ohnishi, Y, Moore, B. S.; Shen, B. (2013) Predictive model for epoxide hydrolase-generated stereochemistry in the biosynthesis of 9-membered enediyne antitumor antibiotics. Biochemistry 52:5217-5224. PMID: 23844627 PDF Huang, S.-X.; Lohman, J. R.; Huang, T.; Shen, B. (2013) A new member of the 4-methylideneimidazole-5-one-containing aminomutase family from the enediyne kedarcidin biosynthetic pathway. Proc. Natl. Acad. Sci. USA 110:8069-8074. PMID: 23633564 [PubMed in process] PDF Ma, M.; Kwong, T.; Lim, S.-K.; Lohman, J. R.; Shen, B. (2013) The post-polyketide synthase steps in iso-migrastatin biosynthesis featuring tailoring enzymes with broad substrate specificity. J. Am. Chem. Soc. 135:2489-2492. Lohman, J. R.; Huang, S.-X.; Horsman, G.P.; Dilfer, P.; Huang, T.; Chen, Y.; Wendt-Pienkowski, E.; Shen, B. (2013) Cloning and sequencing of the kedarcidin biosynthetic gene cluster from Streptoalloteichus sp. ATCC 53650 revealing new insights into biosynthesis of the enediyne family of antitumor antibiotics. Mol. BioSyst. 9:478-91. PMID: 23360970 [PubMed - in process] PDF Lohman, J. R,; Bingman, C. A.; Phillips Jr., G. N.; Shen, B. (2013) The structure of the bifunctional acyltransferase/decarboxylase LnmK from the leinamycin biosynthetic pathway revealing novel activity for a double hot dog fold. Biochemistry 52:902-911. [PubMed] PDF Yu, Z.; Rateb, M. E.; Smanski, M. J.; Peterson, R. M.; Shen, B. (2013) Isolation and structural elucidation of glucoside congeners of platencin from Streptomyces platensis SB12600. J. Antibiot. 66:291-294. PMID: 23361357 PDF Van der Donk, et al. (total of 58 co-authors). (2013) Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Nat. Prod. Rep. 30:108-160. PMID: 23165928 PDF Kurata, S.; Shen, B.; Liu, J. O.; Takeuchi, N.; Kaji, A.; Kaji, H. (2013) Possible steps of complete disassembly of post-termination complex by yeast eEF3 deduced from inhibition by translocation inhibitors. Nucleic Acids Res. 41:264-276. ?[PubMed] PDF Unsin, C. E.-M.; Rajski, S. R.; Shen, B. (2013) “The Role of Genetic Engineering in Natural Product-based Anticancer Drug Discovery” in Natural Products and Cancer Drug Discovery, Koehn, F. E. ed., Springer, New York, NY, pp175-191. PDF Tebbets, B.; Yu, Z.; Stewart, D.; Zhao, L.-X.; Jiang, Y.; Xu, L.-H.; Shen, B.; Klein, B. (2013) Identification of macrotetrolides as antifungal natural products via yeast bioassay: insights into drug spectrum, potency and mode of action. Medical Mycology, 51:280-9. [PubMed] Smanski, M. J.; Casper, J.; Peterson, R. M.; Yu, Z.; Rajski, S. R.; Shen B. (2012) Heterologous expression of the platencin gene cluster yields several platencin congeners. J. Nat. Prod. 75:2158-2167. [PubMed] PDF