Study on Inhibition Mechanism and Rational Design of Protein Phosphatase Inhibitor Tautomycin
| Project/Area Number |
09660108
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 Fac.of Agriculture, Hokkaido Univ.Inst., 農学部, 助手 (00185175)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | tautomycin / tautomycetin / protein phosphatase / inhibitor / ト-トマイシン / ト-トマイセチン |
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| Research Abstract |
Tautomycetin (TMT), an antifungal agent from Streptomyces griseo-chromogenes shows a distinctive biological and structural similarity to tautomycin (TM), which is known as a potent inhibitor of protein phosphatases (PP) type I and 2A.It strongly suggests that TMT is also an inhibitor of PP1 and PP2A and that the structural difference of TMT and TM is exchangeable. In order to obtain pertinent data for this hypothesis and to develop a specific inhibitor for PP1, we studied a total synthesis of TMT and conformational analysis of right fragments of TMT and TM.Biological activities of tautomycin analogs were also examined The right half of tautomycetin were constructed by asymmetric crotylboration as key reactions. Efficient construction of dienone moiety has been achieved by a regioselective hydrostannylation of internal alkyne and the subsequent Stille coupling, Thus, two large subunits for synthesis of TMT were synthesized.
Both molecular mechanics calculations and 'H-NMR data exhibited that tautomycetin right half is present as "bent conformers". Most populated conformer of the tautomycetin right half showed a distinct similarity to the one found in the right half of tautomycin.
Effects of tautomycin and its derivatives on protein phosphatases PP1 and PP2A and their apoptosis-inducing activity on human leukemia Jurkat cells were examined and the relationship between chemical structure and function was discussed.
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Report
(3 results)
Research Products
(6 results)
