Development of PKS biocatalysts on the example of a multi-enzyme cascade for improved synthesis of antifungal polyketides

以多酶级联为例开发 PKS 生物催化剂以改进抗真菌聚酮化合物的合成

• 批准号: 455011838
• 负责人: Professor Dr. Frank Hahn
• 金额: --
• 依托单位: Arbeitsgruppe Organische Chemie (Lebensmittelchemie)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/455011838?language=en
• 关键词: Development; PKS; biocatalysts; example; multi

This project aims to advance the establishment of polyketide synthase (PKS) modules as biocatalysts and to demonstrate the advantages of their use in the total synthesis of natural products. As an example, a multi-enzyme cascade is to be developed, with the PKS module AmbMod4 from the ambruticin biosynthesis at its centre. A tailor-made adaptation of the conditions should enable an optimal interaction of the module with the other enzymatic components. This cascade will find a concrete application in the context of the chemoenzymatic total synthesis of jerangolides. There, it is intended to replace the multi-step, synthetically difficult formation of a vinyltetrahydropyran by an efficient one-pot process, thereby significantly shortening the longest linear sequence. In order to establish the enzyme cascade, the production of AmbMod4 will be optimized and a suitable thioesterase domain will be identified which selectively releases the desired AmbMod4 product while avoiding conceivable side reactions. This would enable preparative biocatalytic reactions with AmbMod4. This cascade is to be gradually extended by a C-methyltransferase and a cyclase and scaled up to the semi-preparative scale.

该项目旨在推进聚酮合酶（PKS）模块作为生物催化剂的建立，并展示其在天然产物全合成中的优势。例如，将开发多酶级联，其中来自安布霉素生物合成的PKS模块AmbMod 4处于其中心。对条件的定制适应应使模块与其他酶组分的最佳相互作用成为可能。该级联反应将在Jerangolides的化学酶促全合成中得到具体应用。在那里，它旨在通过有效的一锅法代替乙烯基四氢吡喃的多步合成困难的形成，从而显著缩短最长的线性序列。为了建立酶级联，将优化AmbMod 4的产生，并且将鉴定合适的硫酯酶结构域，其选择性地释放所需的AmbMod 4产物，同时避免可能的副反应。这将使得能够用AmbMod 4进行制备型生物催化反应。该级联反应将通过C-甲基转移酶和环化酶逐渐扩展，并按比例放大至半制备规模。