ENGINEERED BIOSYNTHESIS OF A COMPLETE MACROLACTONE IN A HETEROLOGOUS HOST
ENGINEERED BIOSYNTHESIS OF A COMPLETE MACROLACTONE IN A HETEROLOGOUS HOST
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DOI：
10.1126/science.8036492
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发表时间：
1994-07-22
期刊：
影响因子：
56.9
通讯作者：
KHOSLA, C
中科院分区：
文献类型：
--
作者：
KAO, CM;KATZ, L;KHOSLA, C
大环聚酮化合物由于其结构的复杂性和药用活性，一直是合成和生物合成化学中的研究热点。在异源宿主中表达完整的6-脱氧齐墩果酸B合酶（DEBS）（10，283个氨基酸）后，在天蓝色链霉菌中合成了大量的6-脱氧齐墩果酸B（6 dEB）（大环内酯抗生素红霉素的糖苷配基）和8，8 α-脱氧齐墩果酸（8，8 α-deoxyoleanderase）（除了甲基侧链代替乙基单元之外，与6 dEB相同的14元内酯环）。生物合成策略利用了一种遗传方法，该方法有助于快速操作DEBS或其他模块化聚酮酶（PKS）的结构，包括在遗传方法不发达的放线菌中发现的那些。从技术的角度来看，这种方法应该允许生物合成产品的合理设计，并可能最终导致通过天然存在的和突变体PKS模块的组合克隆的方式产生不同的聚酮化合物库。
Macrocyclic polyketides have been subjects of great interest in synthetic and biosynthetic chemistry because of their structural complexity and medicinal activities. With expression of the entire 6-deoxyerythronolide B synthase (DEBS) (10,283 amino acids) in a heterologous host, substantial quantities of 6-deoxyerythronolide B (6dEB), the aglycone of the macrolide antibiotic erythromycin, and 8,8a-deoxyoleandolide, a 14-membered lactone ring identical to 6dEB except for a methyl group side chain in place of an ethyl unit, were synthesized in Streptomyces coelicolor. The biosynthetic strategy utilizes a genetic approach that facilitates rapid structural manipulation of DEBS or other modular polyketide synthases (PKSs), including those found in actinomycetes with poorly developed genetic methods. From a technological viewpoint, this approach should allow the rational design of biosynthetic products and may eventually lead to the generation of diverse polyketide libraries by means of combinatorial cloning of naturally occurring and mutant PKS modules.