Biosynthetic studies on a novel 17-membered macro-cyclic compound produced by a Streptomyces strain

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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.