| 1.Research Institution | Kitasato University | |
| 2.Research Area | Integrated Fields | |
| 3.Research Field | Production of Novel Useful Substances through Integration of Life Sciences and Chemistry | |
| 4.Term of Project | FY1996〜FY2000 | |
| 5.Project Number | 96I00304 | |
| 6.Title of Project | Discovery and production of lead compounds for medicines from microorganisms |
| Name | Institution,Department | Title of Position |
| Satoshi Omura | Kitasato Univ., Grad. Sch. Pharm. Sciences | Professor |
8.Core Members
| Names | Institution,Department | Title of Position |
| Haruo Tanaka | Kitasao Univ., School of Pharmaceutical Sciences | Professor |
| Haruo Ikeda | Kitasao Univ., School of Pharmaceutical Sciences | Assoc. Professor |
| Hiroshi Tomoda | The Kitasato Institute, Res. Ctr. Biological Function | Assoc. Director |
9.Cooperating Researchers
| Names | Institution,Department | Title of Position |
| Masahiko Hayashi | The Kitasato Institute, Ctr. Basic Research | Res. Head |
| Mun Chual Rho | JSPS | Researcher |
| Ichiji Namatame | JSPS | Researcher |
10.Summary of Research Results
|
This research project focused on two main themes as follows; 1. Discovery and production of new lead compounds for diseases of human immunodeficiency virus (HIV), cancer, atherosclerosis and inflammation from microorganisms. --- In order to discover lead compounds from microorganisms, original screening systems were conducted by utilizing intact cells with special functions. 1) From screening for anti-HIV substances in a syncytium formation assay system, actinohivin (AH) was isolated from the culture broth of an actinomycete strain K97-0003. AH consists of a 114-amino acid chain that exhibits internal sequence triplication. AH inhibited both T-cell and macrophage tropic syncytium formations. AH was found to bind gp120 by selectively recognizing high-mannose polysaccharide chain of glycoproteins. 2) From screening for anti-atherosclerotic agents in a foam cell formation assay sytem, beauveriolides, phenochalasins and K97-0239 were isolated from fungal and actinomycete culture broths. These inhibitors reduced the number and the size of lipid droplets formed in macrophages. Beauveriolides inhibited the synthesis of cholesteryl ester by blocking acyl-CoA:cholesterol acyltransferase activity specifically. Importantly, beauveriolide proved to be orally active in both LRL receptor knockout mice and apo E knockout mice, reducing atheroma lesion in the aota and heart. 3) From screening for tumor metastasis inhibitors in a cell-cell adhision assay system, macrosphelides (MS) were isolated from the fungal culture broth. MS-A inhibited the binding of sialyl LewisX to E-selectin. Intraperitoneal injection of MS-A also inhibited the pulmonary metastasis of B16/BL6 melanoma in mice. On the other hand, MS-B was found to show immunosuppressive activity in mouse models. The mechanism of immunosuppression of MS-B may differ from those of FK506 and cyclosporine A. 2. Analysis of the biosyhthetic gene of anthelmintic avermectin in Streptomyces avermitilis. --- The entire avermectin biosynthetic gene cluster was cloned and characterized. The gene consists of 18 ORFs in a distance of 82 kb containing polyketide synthases organized as two sets of six modular repeats and post-polyketide modification enzymes. Based on the findings, unnatural avermectin analogs like ivermectin were biosynthesized by manipulating the gene. |
11.Key Words
(1)Microbial metabolites、(2)Lead compounds for medicines、(3)Anti-HIV actinohivin
(4)Anti-atherosclerotic beauveriolide、(5)Anti-metastatic macrosphelide、(6)Anthelmintic
(7)Avermectin、(8)Polyketide biosynthetic gene、(9)Gene manupulation
12.References
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| J. Antibiot | 51 | 1998 | 68-72 | |
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| J. Antibiot. | 51 | 1998 | 1004-1011 | |
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| Journal | Volume | Year | Pages Concerned | |
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| Actinomycetologica | 13 | 1999 | 94-112 | |
| Author | Title of Article | |||
| H. Ikeda, et al. | Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis. | |||
| Journal | Volume | Year | Pages Concerned | |
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| Journal | Volume | Year | Pages Concerned | |
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| Journal | Volume | Year | Pages Concerned | |
| J. Antibiot | 53 | 2000 | 422-425 | |
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| Journal | Volume | Year | Pages Concerned | |
| Antonie van Leeuwenhoek | 78 | 2000 | 107-115 | |
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| Journal | Volume | Year | Pages Concerned | |
| Biol. Pharm. Bull. | 23 | 2000 | 262-264 | |
| Author | Title of Article | |||
| H. Chiba, et al. | Actinohivin, a novel anti-HIV protein that inhibits syncytium formation: isolation, characterization, and biological activities. | |||
| Journal | Volume | Year | Pages Concerned | |
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| J. Inokoshi, et al. | Molecular cloning of actinohivin, a novel anti-HIV protein from an actinomycete, and its expression in Escherichia coli. | |||
| Journal | Volume | Year | Pages Concerned | |
| Biochem. Biophys. Res. Commun. | 281 | 2000 | 1261-1265 | |
| Author | Title of Article | |||
| S. Omura & K. Shiomi | Production of medicines and microbial secondary metabolites | |||
| Journal | Volume | Year | Pages Concerned | |
| Bioscience and Industry | 54 | 1996 | 633-635 | |
| Author | Title of Article | |||
| S. Omura | Antibiotics in the 21st century. | |||
| Journal | Volume | Year | Pages Concerned | |
| Jpn J. Antibiot | 49 | 1996 | 755-765 | |
| Author | Title of Article | |||
| H. Ikeda and S. Omura | Production of useful unnatural products by manupulating biosynthtic genes of microbial secondary metabolites. | |||
| Journal | Volume | Year | Pages Concerned | |
| Kagakutoseibutsu | 34 | 1996 | 761-771 | |
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| H. Ikeda and S. Omura | Avermectin biosynthesis. | |||
| Journal | Volume | Year | Pages Concerned | |
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| Journal | Volume | Year | Pages Concerned | |
| Nippon Nougeikagaku Zassi | 71 | 1997 | 530-534 | |
| Author | Title of Article | |||
| H. Ikeda and S. Omura | Combinatorial biosynthesis of polyketides. | |||
| Journal | Volume | Year | Pages Concerned | |
| Tanpakusitsu Kakusan Kouso | 43 | 1998 | 1265-1277 | |
| Author | Title of Article | |||
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| Journal | Volume | Year | Pages Concerned | |
| Pure Appl. Chem. | 71 | 1999 | 1059-1064 | |
| Author | Title of Article | |||
| S. Omura | Anti-infective agents into the 21st century. | |||
| Journal | Volume | Year | Pages Concerned | |
| Nippon Saikingaku Zassi | 54 | 1999 | 795-813 | |
| Author | Title of Article | |||
| I. Namatame, et al. | Discovery of anti-atherosclerotic agents from microorganisms. | |||
| Journal | Volume | Year | Pages Concerned | |
| Bioscience and Industry | 58 | 2000 | 193-194 | |
| Author | Title of Book | ||
| H. Tanaka and S. Omura | Biotechnology / (Screening of novel receptor-activity compounds of microbial origin) | ||
| Publisher | Year | Pages | |
| VCH Verlargsgesellschaft mbH | 1997 | 107-132 | |
| Author | Title of Book | ||
| H. Tomoda and S. Omura | Enzyme Technologies for Pharmaceutical and Biotechnological Applications/(Screening for inhibitors of lipid metabolism) | ||
| Publisher | Year | Pages | |
| Marcel Dekker Inc., New York | 2001 | 343-378 | |