Bioconversion of milbemycin-related compounds: biosynthetic pathway of milbemycins
K Nonaka1, C Kumasaka, Y Okamoto
1Biomedical Research Laboratories, Sankyo Co., Ltd., Fukushima, Japan.
Abstract:
Streptomyces hygroscopicus subsp. aureolacrimosus SANK 60286 and SANK 60576 produce many kinds of milbemycins. Among them, milbemycin alpha11, alpha14, A3, and A4 have the most effective acaricidal activity. In this study, we investigated the terminal biosynthetic pathway to milbemycin alpha14 and A4 which accumulated as the final products in these strains. Using cerulenin, a specific inhibitor of fatty acid and polyketide biosynthesis, we conducted bioconversion experiments with cultures of several mutants, including milbemycin A4- and alpha14-producing strains. The bioconversions of milbemycin beta6 to milbemycin A4 and milbemycin A4 to milbemycin alpha14 could be identified. For the biosynthesis of milbemycin A4 from milbemycin beta6 in the milbemycin A4-high producing strain, there appeared to be two separate pathways exhibiting different sequences of furan ring formation and C-5 keto reduction steps.
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