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Hot springs and cool natural products Ho Jeong Kwon, Choong Hwan Lee, Hiroyuki Osada, Minoru Yoshida & Masaya Imoto Natural products have played a unique role in providing new tools and insights in chemical biology. The tremendous value of natural products was highlighted by scientists from Korea and Japan at the 4 th Korea-Japan Chemical Biology symposium. The 4th Korea-Japan Chemical Biology (KJCB) symposium was held on May 21–23, 2008 in Nikko, Japan to explore current trends and future directions in natural products–based chemical biology. This symposium featured oral and poster presentations by outstanding scientists from Korea and Japan. Herein we feature some highlights of this two-day meeting, which was filled with a wealth of scientific discussions inspired by the beautiful surroundings at Nikko. History of the KJCB At the 2000 International RIKEN Conference in Japan entitled “Frontiers of Chemistry and Biology,” scientists from Korea and Japan proposed organizing a joint Korea-Japan symposium on chemical biology. Natural products–based chemical biology has historically featured very prominently in both Korea and Japan, and this research has proven to be very useful for developing tools to probe Ho Jeong Kwon is in the Chemical Genomics Laboratory, Department of Biotechnology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Korea. Choong Hwan Lee is in the Division of Bioscience and Biotechnology, Konkuk University, 11-1, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea. Hiroyuki Osada is in the Chemical Biology Department, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Minoru Yoshida is in the Chemical Genomics Research Group, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Masaya Imoto is in the Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan e-mail:
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biological systems and for discovering smallmolecule drug leads. As fields such as genomebased drug discovery gain prominence in the postgenomic era, research into bioactive products is expected to become increasingly important. With the diversity of structure and activity of bioactive compounds produced by microorganisms and plants in both Korea and Japan, studies in these countries can provide unique opportunities for natural products– based research. Against this background, the first KJCB symposium, entitled “Development of Bioactive Substances as Postgenome Science Research,” was held in 2001 in Daejon, Korea to stimulate natural product–based approaches toward
postgenomic research and to encourage collaboration between Japanese and Korean scientists. The second KJCB was held in 2004 in Hakone, Japan, and the third KJCB took place in 2006 in Seoul, Korea. These three KJCB symposia were all held in areas that are famous for hot springs, and hence were dubbed the “hot spring symposia.” Continuing this tradition, the 4th symposium was held in a famous hot spring area in Nikko, Japan. At this KJCB, which we highlight below, 23 Korean scientists and 26 Japanese scientists described recent advances in discovering natural products and in understanding the biological activity, molecular targets and biosynthetic pathways of these bioactive small molecules.
The 4th KJCB meeting was held in Nikko, a famous hot spring area in Japan.
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target. In his presentation, Won Gon Kim (Korea Research Institute of Bioscience and Biotechnology) presented the first microbialderived FabI inhibitors, which included cephalochromin (Fig. 1), a fungal metabolite from Verticillium sp. that was discovered by screening 18,000 microbial extracts4. Three of these talks highlighted that marine microorganisms are a prolific and yet underexploited source for the discovery of new secondary metabolites, and all of these presentations emphasize the impressive chemical diversity of bioactive molecules.
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Discovery of bioactive molecules A number of natural products with unique chemical structures and interesting biological activities were presented at the meeting. Hee Jae Shin (Korea Ocean Research and Development Institute) reported a number of new bioactive compounds, including streptochlorin (Fig. 1), from marine microorganisms that exhibited anticancer, anti-angiogenesis and antimicrobial activities1. Daisuke Uemura (Keio University) presented the isolation of two new compounds, symbiodinolide and symbioimine (Fig. 1), from the symbiotic marine dinoflagellate Symbiodinium sp. (ref.
2). Symbiodinolide is a ‘super-carbon chain compound’ (SCCC) that exhibits potent voltage-dependent N-type Ca2+ channel–opening activity Hiroshi Tomoda (Kitasato University) described the new compounds isobisvertinol (Fig. 1) and quinadolines, which were isolated from the marine-derived fungus Aspergillus clavatonaicus and found to block lipid droplet formation in mouse macrophages3. Further studies have suggested that enzymes involved in cholesteryl ester and triacylglycerol synthesis are the targets of isobisvertinol. FabI, an enoylACP reductase in bacterial fatty acid synthesis, has been well validated as an antibacterial
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Biosynthesis of bioactive molecules Natural product biosynthesis often involves elaborate chemical mechanisms. Four talks at the meeting illustrated exciting advances in understanding the enzymatic transformations involved in creating bioactive molecules. Eung-Soo Kim and colleagues (Inha University) used a polyene cytochrome P450 hydroxylase (CYP)-specific PCR screening approach that enabled them to identify a cryptic nystatin-like polyene compound in Pseudonocardia autotrophica KCTC9441. These results suggest that the polyene CYPspecific genome screening strategy may constitute an efficient method for isolating potentially valuable new polyene-producing actinomycetes5. In staurosporine biosynthesis, the cytochrome P450 enzyme P450StaP is involved in a key step in formation of the indolocarbazole core from chromopyrrolic acid. Hiroyasu Onaka (Toyama Prefectural University) presented the crystal structure of P450StaP, which suggested a mechanism in which the heme of StaP removes two electrons from the indole ring to generate an indole cation radical, and intramolecular radical coupling then forms the C-C bond of the indolocarbazole core6. Jae Kyung Sohng (Sun Moon University) reported on the heterologous expression of genes implicated in aminoglycoside formation in Streptomyces kanamyticus and Micromonospora echinospora in a non-aminoglycoside–producing strain of Streptomyces venezuelae. This approach enabled elucidation of the biosynthetic pathway based on two new aminoglycoside derivatives of kanamycin B and gentamicin A2 (ref. 7). Finally, on the basis of tracer and feeding experiments, Tohru Dairi (Toyama Prefectural University) presented the last step in a new menaquinone biosynthetic pathway operating in some microorganisms8. These four talks highlighted new insights into synthetic genes and their application to enzymatic transformations, potentially providing new opportunities for the biosynthesis of natural and non-natural analogs of natural products.
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m e e t i n g r e por t Mechanism of action In the final section, four presentations described exciting advances in understanding the modes of action of natural products. Choong Hwan Lee (Konkuk University) reported on LC-MS/MS–based microbial metabolomic profiling of chemotactic fungi and bacteria to develop a phylogenetic metabolome database as a new chemical biology resource. Using a chemical genetic approach, Minoru Yoshida (RIKEN) presented the identification of SF3b, a subcomplex of U2 snRNP in the spliceosome, as the cellular target of the antitumor natural product FR901464 and its methylated derivative spliceostatin A (ref. 9). Importantly, treatment of cells with these compounds resulted in not only the accumulation of unspliced pre-mRNAs but also the induction of premRNA translation into proteins, resulting in a mechanistic model in which SF3b acts as a factor important for the nuclear retention of pre-mRNA. Ho Jeong Kwon (Yonsei University) presented results identifying aminopeptidase N (APN), a membranebound metalloproteinase, as a biologically relevant target for the anti-angiogenic activity of curcumin, which gives the characteristic yellow color to turmeric. He also reported several pharmacologically safe curcumin derivatives with novel biological activities and targets10. A topic that attracted significant interest was presented by Makoto Kawatani (RIKEN). Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents11. By screening their chemical library (RIKEN NPDepo), Makoto Kawatani and colleagues found that methylgerfelin (M-GFN), the methyl ester of gerfelin (GFN), which is isolated from the fungal strain Beauveria felina QN22047, suppresses osteoclastogenesis. By using a photocrosslinked M-GFN affinity matrix, they identified glyoxalase I (GLO1) as the molecular target of M-GFN for osteoclastogenesis inhibition. Further, the cocrystal structure of the GLO1–M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1 (Fig. 2). These talks demonstrated the unique role of natural products as molecular probes to explore new biological systems and to provide new opportunities for the development of small-molecule drug leads.
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Natural product ‘translational research’ Finally, a special lecture was provided by Takao Yamori (Japanese Foundation for Cancer Research). Using his newly developed panel of 39 human cancer cell lines (JFCR39) and the COMPARE algorithm, which is based on chemosensitivity measurements from the JFCR39 according to the methodology for NCI60, he presented the identification of new bioactive compounds and their molecular targets. The most prominent outcome from this evaluation was the identification of the new phosphatidylinositol-3-OH kinase inhibitor ZSTK474 (Fig. 1), which showed strong therapeutic efficacy against human cancer xenografts without severe toxicity12. Young scientists’ presentation As one of the important features of this joint symposium, promising young scientists from both countries gave oral presentations of their latest results. Meeyeon Oh (Yonsei University) described the apoptosis induction activity of a new synthetic histone deacetylase (HDAC) inhibitor, HNHA (Fig. 1)13, and she further demonstrated that HNHA induces apoptosis via a mitochondria-mediated pathway. Through a screening approach, Etsu Tashiro and Masaya Imoto (Keio University) identified the small molecules trierixin14 and quinotrierixin from Streptomyces spp. strains as protective against endoplasmic reticulum stress-induced X-box binding protein 1 (XBP1) activation and glucose-regulated protein (GRP78) upregulation and further showed that these small molecules strongly suppress tumor cell growth. Finally, Sung Ryeol Park and Yeo Joon Yoon (Ewha Womans University) presented recent progress in the heterologous expression of a large polyketide biosynthetic gene cluster from Streptomycete sp. for the production of tylosin derivatives (Fig. 1)15. Besides these invited presentations, over 30 posters generated great interest among participants, providing further opportunities for young scientists to discuss their work. The hot spring symposia flow on Chemical biologists of Korea and Japan have initiated and developed this unique forum to cultivate interactions and friendship between the two countries through their common interest in science, particularly in natural products–based chemical biology. In this sense, the meeting has great energy like a hot
Figure 2 Cocrystal structure of mouse GLO1–MGFN complex. Mouse GLO1 and M-GFN are drawn in ribbon and CPK models, respectively. Gray spheres represent zinc ions.
spring, mixing not only the fields of chemistry and biology but also Korean and Japanese scientists. Now the energy generated from the “Kinugawa-stream” of Nikko will flow toward the 5th KJCB meeting, which will be held in 2010 at a hot spring in Korea. ACKNOWLEDGMENTS The meeting was supported by Keio University and the Korean Society for Microbiology and Biotechnology. The organizers of both countries are grateful for the great contribution of all participants, which made the symposium incredibly successful. 1. Shin, H.J. et al. J. Microbiol. Biotechnol. 17, 1403– 1406 (2007). 2. Kita, M. et al. Tetrahedron 63, 6241–6251 (2007). 3. Koyama, N., Ohshiro, T., Tomoda, H. & Omura, S. Org. Lett. 9, 425–428 (2007). 4. Zheng, C.J. et al. Biochem. Biophys. Res. Commun. 362, 1107–1112 (2007). 5. Lee, M.Y., Myong, J.S., Park, H.J., Han, K. & Kim, E.S. J. Ind. Microbiol. Biotechnol. 33, 84–87 (2006). 6. Makino, M. et al. Proc. Natl. Acad. Sci. USA 104, 11591–11596 (2007). 7. Park, J.W. et al. Proc. Natl. Acad. Sci. USA 105, 8399– 8404 (2008). 8. Seto, H. et al. J. Am. Chem. Soc. 130, 5614–5615 (2008). 9. Kaida, D. et al. Nat. Chem. Biol. 3, 576–583 (2007). 10. Shim, J.S. et al. Chem. Biol. 10, 695–704 (2003). 11. Woo, J.-T. et al. Proc. Natl. Acad. Sci. USA 103, 4729– 4734 (2006). 12. Yaguchi, S. et al. J. Natl. Cancer Inst. 98, 545–556 (2006). 13. Kim, D.H. et al. Biochem. Biophys. Res. Commun. 356, 233–238 (2007). 14. Tashiro, E. et al. J. Antibiot. (Tokyo) 60, 547–553 (2007). 15. Jung, W.S. et al. Appl. Environ. Microbiol. 74, 1972– 1979 (2008).
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