De Novo Design and Implementation of a Tandem Acyl Carrier Protein Domain in a Type I Modular Polyketide Synthase,ACS Chemical Biology

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De Novo Design and Implementation of a Tandem Acyl Carrier Protein Domain in a Type I Modular Polyketide Synthase
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-10-24 00:00:00 , DOI: 10.1021/acschembio.8b00896
Zilong Wang _{1,

2,

3} , Saket R. Bagde ₁ , Gerardo Zavala ₁ , Tsutomu Matsui ₄ , Xi Chen ₅ , Chu-Young Kim _{1,

6}

Affiliation

During polyketide and fatty acid biosynthesis, the growing acyl chain is attached to the acyl carrier protein via a thioester linkage. The acyl carrier protein interacts with other enzymes that perform chain elongation and chain modification on the bound acyl chain. Most type I polyketide synthases and fatty acid synthases contain only one acyl carrier protein. However, polyunsaturated fatty acid synthases from deep-sea bacteria contain anywhere from two to nine acyl carrier proteins. Recent studies have shown that this tandem acyl carrier protein feature is responsible for the unusually high fatty acid production rate of deep-sea bacteria. To investigate if a similar strategy can be used to increase the production rate of type I polyketide synthases, a 3×ACP domain was rationally designed and genetically installed in module 6 of 6-deoxyerythronolide B synthase, which is a prototypical type I modular polyketide synthase that naturally harbors just one acyl carrier protein. This modification resulted in an ∼2.5-fold increase in the total amount of polyketide produced in vitro, demonstrating that installing a tandem acyl carrier domain in a type I polyketide synthase is an effective strategy for enhancing the rate of polyketide natural product biosynthesis.

中文翻译：

从头设计和实现在I型模块化聚酮化合物合酶中的串联酰基载体蛋白结构域。

在聚酮化合物和脂肪酸的生物合成过程中，不断增长的酰基链通过硫酯键连接到酰基载体蛋白上。酰基载体蛋白与其他酶相互作用，这些酶在结合的酰基链上进行链延长和链修饰。大多数I型聚酮化合物合酶和脂肪酸合酶仅包含一种酰基载体蛋白。但是，来自深海细菌的多不饱和脂肪酸合酶含有2至9个酰基载体蛋白。最近的研究表明，这种串联的酰基载体蛋白特征是造成深海细菌异常高的脂肪酸产生速率的原因。为了研究是否可以使用类似的策略来提高I型聚酮化合物合酶的生产率，合理设计了一个3×ACP结构域，并将其遗传安装在6-脱氧赤藓醇内酯B合酶的模块6中，该模块是典型的I型模块化聚酮化合物合酶，其天然仅包含一种酰基载体蛋白。这种修饰导致产生的聚酮化合物总量增加约2.5倍在体外，证明在I型聚酮化合物合酶中安装串联酰基载体结构域是提高聚酮化合物天然产物生物合成速率的有效策略。

更新日期：2018-10-24

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