| Project/Area Number |
12045268
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Science and Engineering
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| Research Institution | RIKEN |
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Principal Investigator |
OSADA Hiroyuki RIKEN, Discovery Research Institute, Chief Scientist, 抗生物質研究室, 主任研究員 (80160836)
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| Co-Investigator(Kenkyū-buntansha) |
SIMIZU Siro RIKEN, Discovery Research Institute, Scientist, 抗生物質研究室, 研究員 (30312268)
USUI Takeo RIKEN, Discovery Research Institute, Scientist, 抗生物質研究室, 研究員 (60281648)
KAKEYA Hideaki RIKEN, Discovery Research Institute, Scientist, 抗生物質研究室, 研究員 (00270596)
SEKIYAMA Yasuyo RIKEN, Discovery Research Institute, Special Postdoctoral Researcher, 抗生物質研究室, 基礎科学特別研究員 (60342804)
MACHIDA Kiyotaka RIKEN, Discovery Research Institute, Special Postdoctoral Researcher, 抗生物質研究室, 基礎科学特別研究員 (30332266)
HAMAMOTO Ryuji 東京大学, 医科学研究所, 助手 (80321800)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥19,800,000 (Direct Cost: ¥19,800,000)
Fiscal Year 2002: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2001: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2000: ¥7,800,000 (Direct Cost: ¥7,800,000)
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| Keywords | phoslactomycin / phosphatase / inhibitor / biosynthesis / apoptosis / dephosphorylation / isoavenaciolide / Bcl-2 / リン酸化 / 4-isoavenaciolide / VHR / Michael付加 / 活性中心 / RK-682 / 分子設計 / テトロン酸 |
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| Research Abstract |
Proteins involved in the signal transduction are regulated by phosphorylation/dephosphorylation during a process of proliferation, differentiation and apoptosis.Many selective inhibitors for protein kinases have been developed, however development of selective phosphatase inhibitors has not been achieved yet.To resolve this problem, I have tried to develop phosphatase inhibitors.
1.4-isovavenaciolide was isolated as an inhibitor of the VHR protein tyrosine phosphatase. As 4-isoavenaciolide possesses a reactive exo-methylene moiety, it is possible that 4-isoavenaciolide inhibits VHR through the direct modification of a cysteine residue in the catalytic site.Since dual-specificity phosphatases have a consensus CXXXXXR motif in the catalytic site, dual-specificity phosphatases are sensitive to 4-isoavenaciolide.
2.Phoslactomycins (PLMs) produced by Streptomyces, are potent and selective inhibitors of serine threonine phosphatases, PP2A.Incorporation studies with stable isotope labeling cyclohexanecarboxylic acid (CHC) indicated that the six PLM analoges (PLM A-F) made by Streptomyces sp.HK-803 are all biosynthesized from a CHC starter unit.Hydroxylation of the CHC-derived side chain of PLM B and a subsequent esterification produces the remaining PLM analogs.The entire 75 kb PLM biosynthetic gene cluster of the producing strain was cloned, sequenced and analyzed.Thecluster contains six genes (plml-7) which comprise the loading domain and seven extension modules of the type I modular PLM polyketide synthase.
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