Biosynthetic Machinery and Diversity-oriented Engineered Biosynthesis of Antimycin
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- Zhang Lihan
- 東大院薬
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- Yan Yan
- 上海有機化学研
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- Mori Takahiro
- 東大院薬
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- Awakawa Takayoshi
- 東大院薬
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- Liu Wen
- 上海有機化学研
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- Abe Ikuro
- 東大院薬
Bibliographic Information
- Other Title
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- アンチマイシン生合成マシナリーの解明と多様性指向型合成生物学
Description
<p> Antimycin antibiotics are structurally complex, medicinally important compounds produced by Streptomyces strains. With aminobenzoate moiety and 9-membered dilactone moiety, antimycins are potent inhibitor of respiration exhibiting strong antitumor activity. Recently we identified the biosynthetic pathway of antimycins and characterized the two enzymes; an acyltransferase AntB, for C8 acylation, and a crotonyl CoA reductase/carboxylase (CCR) AntE, for C7 side chain branching. By in vivo and in vitro analysis, we revealed that they are extremely promiscuous in the substrate recognition, exemplified by the incorporation of fluorotriptophan and cinnamoic acid. Moreover, by multiplexing in vivo fermentation and in vitro enzyme reaction using different unnatural substrates, we successfully produced >300 new antimycin analogs. We also solved the crystal structure of AntE, which serves as a key enzyme in providing unnaturally substituted malonyl-CoAs for the use in PKS extender units. The structure-based engineering of AntE expanded its substrate specificity to further incorporate bulky unnatural substrates such as p-coumaroyl-CoA and even indolylallyl-CoA. It is notable that AntE is the first CCR enzyme catalyzing carboxylation of substituted-aryl substrates. The AntE mutant with larger substrate scope thus is a promising biocatalyst for carboxylation reaction, and in vivo fermentation utilizing AntE V350G successully produced novel arene-bearing antimycins. The fermentation process described here is simple, scalable, and cost efficient compared with organic synthesis of antimycins. Our result demonstrates the power of biosynthesis in the production of highly complex natural product analogs. </p>
Journal
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- Symposium on the Chemistry of Natural Products, symposium papers
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Symposium on the Chemistry of Natural Products, symposium papers 58 (0), Oral33-, 2016
Symposium on the Chemistry of Natural Products Steering Committee
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Details 詳細情報について
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- CRID
- 1390564227317657472
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- NII Article ID
- 130007722867
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- ISSN
- 24331856
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- Text Lang
- ja
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- Data Source
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- JaLC
- CiNii Articles
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- Abstract License Flag
- Disallowed