2007 Fiscal Year Final Research Report Summary
Studies on the Mechanism of Constructing Molecular Skeletons of Bioactive Polyether Metabolites
| Project/Area Number |
17208010
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioproduction chemistry/Bioorganic chemistry
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| Research Institution | Hokkaido University |
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Principal Investigator |
OIKAWA Hideaki Hokkaido University, Faculty of Scienee, Professor (00185175)
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| Co-Investigator(Kenkyū-buntansha) |
OGURI Hiroki Hokkaido University, Faculty of Science, Associate Prof. (80311546)
TOKIWANO Tetsuo Hokkaido University, Faculty of Science, Assistant Prof. (50312343)
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| Project Period (FY) |
2005 – 2007
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| Keywords | polyethers / biosynthesis / polyketides / cyclase / epoxidase |
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| Research Abstract |
Naturally occurring polyether metabolites show a broad range of biological activities and have been isolated from a number of organisms including soil bacteria (ionophore antibiotics), marine dinoflagelate (ladder polyether toxins), marine algae (triterpenes) and annonaceae plants (antitumor acetogenins). In the biosynthesis of polyether metabolites, it is proposed that a polyene precursor is stereoselectively epoxidized and then the subsequent sequential ring openings would afford polyether skeleton. This insightful hypothesis was supported by feeding experiments with isotopically labeled precursors in the biosynthesis of ionophore antibiotics. Recent genetic studies on monensin biosynththesis provided further supports for this hypothesis. Although enormous efforts to prove this hypothesis have been made, direct evidence on these enzymatic transformations has not been obtained. In this project, detailed biosynthetic studies on lasalocid A, an anticoccidium agent from Stretomyces lasaliensis, has carried out to elucidate the enzymatic construction of polyether skeleton.
At first, we have succeeded identification of lasalocid biosynthetic gene cluster spanning 82 kb, and have also developed the stereocontroled synthesis of prelasalocid and its epoxide, which are plausible biosynthetic precursors of lasalocid. The most interesting feature in the polyether formation of lasalocid is an energetically disfavored 6-endo selective cyclization. Our efforts on enzymatic conversions of plausible biosynthetic precursors with the enzymes Lsd18 and Lsd19 overexpressed in Escherichia coli unambiguously showed that complex molecular skeleton of lasalocid is constructed by a sequencial ring opening of the corresponding epoxides with a single epoxide hydrolase Lsd19. This is the first example of the enzymatic formation of polyether skeleton.
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[Presentation] ポリエーテル系抗生物質ラサロシドの生合成研究2006
Author(s)
右田, 章・大栗, 博毅・常盤野, 哲生・渡部, 万美・七條, 好宏・廣瀬, 雄己・渡辺, 賢二・木梨, 陽康・及川, 英秋
Organizer
第48回天然有機化合物討論会
Place of Presentation
仙台
Year and Date
2006-10-14
Description
「研究成果報告書概要(和文)」より
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