53(P-21) 生合成工学的な機能付加による新規ポリケチド化合物の創製(ポスター発表の部)

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Avermectin (1), milbemycin (2) and nemadectin (1) are a series of 16-membered macrocyclic lactones produced by Streptomyces strains and they have potent antiparasitic and broad-spectrum activity against nematode and arthropod parasites. Milbemycin (2) and nemadectin (3) are structurally related to avermectin (1) but former two compounds lack the disaccharide at C13. In many cases, the sugar moiety of complex polyketide compounds is important for the biological activities. Since removal of both sugars of avermectin reduces the antiparasitic activity, introducing the sugar moiety to milbemycin or nemadectin will be useful for the improvement of their biological activities. Although avermectin has a substituent (hydroxyl residue; the residue is glycosylated at the later stage of biosynthesis) at C13, there are no substituents at C13 of nemadectin. These differences depend on the composition of catalytic domains in the polyketide synthases (PKSs). The genetic alternation of the PKS gene(s) by gene manipulation will be able to introduce the rational modification of polyketide structure. Two approaches were done for the production of C13-O-glycosylated nemadectin. Two genes for nemadectin PKSs (nemA3 and nemA4) were inactivated by the insertion mutation in the chromosome of S. cyaneogriseus and the mutants produced C13-hydroxylnemadectin (4) by introducing complementary PKS genes, aveA3 and aveA4, of S. avermitilis. Ultimately, the recombinant strains carrying genes involving L-oleandrose biosynthesis and the glycosylation produced the novel C13-O-L-oleandrosyl-L-oleandrosylnemadectin (5). The biologocal activity of the novel compound (5) was 180-fold higher than that of nemadectin (3) or C13-hydroxynemadectin (4).
天然有機化合物討論会の論文
2003-09-01

53(P-21) 生合成工学的な機能付加による新規ポリケチド化合物の創製(ポスター発表の部)

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