2007 Fiscal Year Final Research Report Summary
Biosynthetic studies on a novel 17-membered macro-cyclic compound produced by a Streptomyces strain
| Project/Area Number |
18580101
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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 | The University of Tokyo |
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Principal Investigator |
KUZUYAMA Tomohisa The University of Tokyo, Biotechnology Research Center, Associate Professor (30280952)
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| Co-Investigator(Kenkyū-buntansha) |
KUDO Fumitaka Tokyo Institute of Technology, Graduate school of Science, Assistant Professor (00361783)
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| Project Period (FY) |
2006 – 2007
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| Keywords | versipelostatin / macro-cyclic compound / gene cluster / cloning / Streptomyces |
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| Research Abstract |
Versipelostatin (VST) produced by Streptomyces versipellis 4083-SVS6 is a novel down regulator of grp78 gene expression in mammalian cells. In order to clone the VST biosynthetic gene cluster, we first cloned the gene for dTDP-D-glclose 4, 6-dehydrogenase (DOH), which is a key enzyme for the biosynthesis of a sugar moiety of VST. Next, we cloned a 30-kb cosmid containing the DOH gene. Sequence analysis revealed that the gene cluster consists of 17 genes including the DOH gene and α-D-glucose 1-phosphate thymidylyltransferase. However, we were unable to identify a glycosyltransferase in the gene cluster. Cloning of entire gene cluster for VST is our next main study.
In addition to the cloning study, we successfully isolated four novel VST analogues, VSTs B-E, from the culture broth of S. versipellis 4083-SVS6. Those structures were determined on the basis of extensive 1D, 2D NMR and MS spectroscopic analyses. The inhibitory activity of the isolated compounds against GRP78 expression induced by 2-deoxyglucose was evaluated. Of them, VST D showed the most potent activity with an IC_<50> value of 4.3 μM, comparable to that of 1 (IC50 = 3.5 μM). These results suggested that the α-L-oleandropyranosyl (1→4)-β-D-digitoxopyranosyl residue in sugar moiety might play an important role for the inhibitory activity.
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