In Focus pubs.acs.org/acschemicalbiology
The 7th Japan-Korea Chemical Biology Symposium: Chemical Biology of Natural Bioactive Molecules Ramesh Prasad Pandey,† Ho Jeong Kwon,§ Jong Seog Ahn,‡ Hiroyuki Osada,∥ and Jae Kyung Sohng*,† †
Institute of Biomolecule Reconstruction, Sun Moon University, Asansi, Chungnam 336-708, Korea Chemical Genomics National Research Laboratory, Department of Biotechnology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749, Korea ‡ Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochangeup, Cheongwongun, Chungcheongbukdo 363-883, Korea ∥ Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, and Antibiotics Laboratory, 2-1 Hirosawa, Wako-shi 351-0198, Japan §
ABSTRACT: Natural bioactive molecules possess supreme chemical diversity and drug-like properties and are an important source for drug lead compounds. At the seventh Japan-Korea Chemical Biology Symposium at Jeju Island, Korea, chemical biologists from Korea and Japan highlighted the remarkable features of natural products and their significance. and fifty-two poster presentations. The symposium was divided into three sectors: discovery, biosynthesis, and mechanism of bioactive molecules. Moreover, an open group discussion between students, young scientists, and chemical biology experts resulted in the sharing of ideas and generation of new collaborations.
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he seventh Japan-Korea Chemical Biology (JKCB) symposium was held on February 9−11, 2014 at the beautiful volcanic Jeju Island, Korea, a UNESCO World Heritage Site (see Figure 1). The theme of this meeting was “Discovery and Biosynthesis of Bioactive Molecules” to explore the novel lead compounds and their targets to develop them as a drug candidates. Well-renowned chemical biologists and young researchers from Korea and Japan gathered to discuss novel experimental designs and findings and to troubleshoot technical problems in the field of chemical biology and application of newly synthesized compounds. The meeting particularly helped scientists share their ideas among colleagues, expand their network by collaboration, and interact directly with peers from the chemical biology community.
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DISCOVERY OF BIOACTIVE MOLECULES A wide array of novel and biologically potent natural products from diverse microbial sources were introduced during the symposium. A high-throughput screening approach using the world’s largest natural product library was widely discussed. Kazuo Shin-ya (National Institute of Advanced Industrial Science and Technology, AIST, Tokyo, Japan) described a natural library covering more than 300,000 compounds from around the world composed of small molecules from Actinomycetes, fungi, bacteria, plant, and marine organisms, which could help in extensive metabolomics studies of new microorganisms. Databases consisting of a large number of metabolites with diverse chemical structures will certainly advance chemical biology research. Similarly, Hyuncheol Oh (Wonkwang University, Korea) explored the identification of bioactive metabolites of high potential for industrial application, e.g., Ramalin from Ramalina terebrata, Antarctic lichen (Figure 2) isolated from polar terrestrial environments.2 Organisms such as lichens and fungi found in distinctive ecosystems have a unique ability to produce novel pharmaceutical chemotypes. In a separate talk, Hiroshi Tomoda (Kitasato University, Japan) introduced pyripyropene A derivatives (Figure 2) produced by Asperigillus sp. FO-1289 as highly selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) enzyme inhibitors. The in vivo efficacy of pyripyropene analogues was studied in depth using apolipoprotein E (Apoe−/−) knockout mice models for development as potentially novel anti-athersclerotic agents.3 Together, these talks highlighted the possibility of exploring
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BACKGROUND OF THE JKCB SYMPOSIUM The JKCB symposium was initiated in 2001 in Daejeon, Korea with the title of “Development of Bioactive Substances as Postgenome Science Research”. This meeting focused on discussions regarding the generation of novel potent bioactive secondary metabolites by applying postgenomic research approaches. The first JKCB symposium facilitated collaborative work between chemical biologists from these two Asian countries. This natural products-based symposium became the foundation for the sharing of ideas and designing of new hypotheses to explore the biosynthesis of biologically potent natural metabolites from diverse sources, including microbial fermentations. After a hiatus of three years, a second JKCB symposium was held in Hakone, Japan, and the third edition of this symposium was organized in Seoul, Korea in 2006. Following the trend of discussing recent advancements in chemical biology, a fourth JKCB symposium was held in the spring of 2008 in Nikko, Japan;1 fifth and sixth symposiums were held in Busan, Korea, in 2010 and Sapporo, Japan in 2012. At the seventh JKCB symposium spanning 2 days, 18 oral presentations were scheduled along with four young scientists © 2014 American Chemical Society
Published: May 16, 2014 1070
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Figure 1. Mt. Halla is the tallest volcanic mountain in Jeju, South Korea. The picture captures the snow flowers of Mt. Halla in winter. Photo credit: Jae Kyung Sohng.
(NPP) from Pseudonocardia autotrophica, which could be developed as an antifungal antibiotic. Finally, Jae Kyung Sohng (Sun Moon University, Korea) revealed the application of highly flexible glycosyltransferase from Bacillus licheniformis to produce diverse Epothilone A glycosides7 (Figure 2) having superior anti-cancer properties with greater bioavailability. Interestingly, he reported the reconstruction of Escherichia coli microbial cell factories applying metabolic engineering and synthetic biology tools to produce a wide array of diverse natural product glycosides using plant and bacterial glycosyltransferases.8,9 These aforementioned four presenters demonstrated new insights into the exploration of biosynthetic pathways of diverse kinds of therapeutically important natural products and their significance in the production of natural and non-natural derivatives using enzymatic and microbial transformation reactions. In fact, the profound study of biosynthetic pathways and application of recently developed metabolic and synthetic tools will undoubtedly help to produce next generation bioactive compounds for the treatment of fatal diseases.
diverse, novel, and highly useful compounds/secondary metabolites from microbes isolated from new environments and emphasized the chemical diversity in nature. In addition, Hiroyuki Osada (RIKEN, Japan) discussed the achievements of the RIKEN chemical biology research group, a prolific international collaboration, which established the RIKEN Natural Products Depository (RIKEN NPDepo) to discover new compounds and for target identification toward their development as drug candidates.
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BIOSYNTHESIS OF BIOACTIVE MOLECULES The elucidation of the biosynthetic mechanism of secondary metabolites by identifying metabolic gene clusters and their characterization is an important aspect in chemical biology. The awakening of silent biosynthetic pathways could help in discovery of cryptic metabolites. Haruo Ikeda (Kitasato University, Japan) shed light on the development of industrially sound, Streptomyces avermitilis based clean versatile heterologous expression hosts to produce streptomycin of S. griseus IFO 13350, cephamycin C of S. clavuligerus ATCC 27064, and pladienolide of S. platensis Mer-11107 by genome engineering (large deletion of nonessential genes).4,5 Such genome minimized hosts have been found to feasibly produce more than 20 different heterologous metabolites. These include production of plant terpenoid derivatives such as amorphidiene in large amount, since primary metabolism seems to be efficiently exploited to generate precursors of exogenous biosynthetic gene clusters. Shunji Takahashi (RIKEN, Japan) explained the in vitro biosynthesis of isoleucyl-tRNA synthetase targeting anti-tumor reveromycin A using heterologously expressed purified enzymes.6 Meanwhile, Eung-Soo Kim (Inha University, Korea) focused on genome mining of rare actinomycetes for exploring the biosynthesis of cryptic polyene macrolide, namely, Nystatin-like Pseudonocardia Polyene
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MECHANISM OF ACTION During the third and last session of seventh JKCB symposium, four chemical biology experts were scheduled to talk on new biological advances toward understanding the mechanism of action of bioactive molecules. At the beginning of this session, Masaya Imoto (Keio University, Japan) talked about a newly identified molecular target to prevent tumor metastasis. Imoto and colleagues found that 5-lipoxygenase (5-LOX) and cysteinyl leukotriene receptor 1 (CysLT1) regulate epidermal growth factor-induced cell migration via T-cell lymphoma invasion and metastasisinducing protein 1 upregulation and Rac1 activation.10 They also found the CysLT1 antagonist blocked the effects caused by 1071
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Figure 2. Chemical structures and selected figures presented in the symposium.
intervenolin (Figure 2), isolated from Nocardia sp. ML96-86F2, as a new anti-tumor compound. The in vivo study on xenograft models of human gastric cancer cells and MDR-expressing colorectal cancer cells showed that intervenolin and its derivatives possess anti-tumor activities; however, the mechanism of action of the molecule is under investigation. The same compounds were also found to exert anti-Helicobacter pylori activity.12,13 These talks elucidated the mechanism of bioactive natural products on cancer treatment. Such advancements in natural products and their mode of action will certainly help to explore novel biological systems for the development of new
the leukotriene C4 produced by 5-LOX mediated Rac1 activation as well as cell migration, thus suggesting CysLT1 as a new potential molecular target for anti-metastatic therapy. Furthermore, he focused on Montelukast as one of the potent CysLT1 antagonists, which could be used for preventing metastasis. Injae Shin’s (Yonsei University, Korea) presentation focused on small molecules such as apoptozole (Figure 2) and imidazole derivatives that induce caspase-dependent apoptosis. This Hsp70 inhibitor blocks the interaction of Hsp-70 with Apaf-1 but does not affect the interaction with ASK1, JNK, Bax, and AIF, thereby inducing caspase-dependent apoptosis.11 Similarly, Manabu Kawada (BIKAKEN, Japan) introduced 1072
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struction (iBR), Sun Moon University (2011-0031960); Chemical Genomics NRL, Yonsei University (NRF-20100017984); Open Translational Research Center for Innovative Drug (OTRCID), Dongguk University, and The Korean Society for Microbiology and Biotechnology. The organizers of both countries are grateful for the active participation of researchers from Japan at the symposium despite the heavy snow storm in Japan.
lead compounds and targets for the treatment of different diseases.
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YOUNG SCIENTISTS’ PRESENTATION Besides the aforementioned oral presentations, four young scientists were selected to present their recent results at this seventh JKCB symposium. Akihiro Ito (RIKEN, Japan) uncovered novel roles for Keap1 in cortactin-mediated cell migration and found an alternative, SIRT2-dependent molecular mechanism by which acetylation of cortactin downregulates cell migration through Keap1. Moreover, the findings strongly suggest that SIRT2 could be a promising therapeutic target for invasive cancers. Another young scientist presenter, Masayoshi Arai (Osaka University, Japan), spoke about the creation of novel drug target for cancer chemotherapy by the study of Furospinosulin-1 (Figure 2), a hypoxia-selective growth inhibitor against cancer cells.14 Furospinosulin-1, a furanosesterterpene, was isolated from the Indonesian marine sponge, Dactylospongia elegans, during screening for hypoxiaselective growth inhibitors. Sang-Jip Nam (Ewha Womans University, Korea) presented the isolation, characterization, and biological activities of ansalactam A and merochlorins A−D. Ansalactam A comprises an unusual spiro γ-lactam moiety and a distinctive isobutyryl polyketide fragment, whereas merochlorins A−D were shown to possess novel chemical skeletons unrelated to known bacterial agents from marine Streptomyces sp. strain CNH-189. Lastly, Yoon Sun Cho (Yonsei University, Korea) introduced the discovery and application of a novel autophagy inducer, called “autophagonizer” (Figure 2).15 The new autophagy-inducing mechanism of action of autophagonizer was identified using Multi-Omics-based Target Identification and Validation (MOTIV system) including ORFeome technology, which is the collection of the entire overexpressed open reading frames of Schizosaccharomyces pombe and Drug Affinity Responsive Target Stability (DARTS) assay for validation.16 In addition to these presentations, more than 50 posters were enthusiastically presented by scientists and students from both countries, demonstrating their active interest in chemical biology research. Awards were handed out to the presenters of the six best posters to encourage research activities of young chemical biologists in both countries. To conclude the symposium, Hiroyuki Osada (RIKEN, Japan) summarized the accomplishments of this noteworthy symposium. He acknowledged his colleagues, scientists, and students from Japan and Korea for their active participation. Moreover, he shared his experiences, achievements, and the benefits of international collaboration in research. Following these concluding remarks, all participants joined in a highly anticipated excursion of Jeju Island and touring the “three plenties”. Along with the speed of the tour bus, the high-speed chilled wind of Jeju Island blew toward Japan, the venue for the eighth JKCB symposium to be held in 2016.
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
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ACKNOWLEDGMENTS The meeting was sponsored by Intelligent Synthetic Biology Center; KRIBB_RIKEN Collaboration Research Center for Chemical Biology, KRIBB; Institute of Biomolecule Recon1073
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a furanosesterterpene isolated from an Indonesian marine sponge. ChemMedChem. 5, 1919−1926. (15) Choi, I. K., Cho, Y. S., Jung, H. J., and Kwon, H. J. (2010) Autophagonizer, a novel synthetic small molecule, induces autophagic cell death. Biochem. Biophys. Res. Commun. 393, 849−854. (16) Cho, Y. S., and Kwon, H. J. (2012) Identification and validation of bioactive small molecule target through phenotypic screening. Bioorg. Med. Chem. 20, 1922−1928.
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