Chemoinformatic-Guided Engineering of Polyketide Synthases.
Chemoinformatic-Guided Engineering of Polyketide Synthases.
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聚酮化合物合成酶的化学信息学指导工程。
DOI：
10.1021/jacs.0c02549
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发表时间：
2020
影响因子：
15
通讯作者：
Her
中科院分区：
文献类型：
--
作者：
Zargar,Amin;Lal,Ravi;Valencia,Luis;Wang,Jessica;Backman,TylerWilliamH;Cruz-Morales,Pablo;Kothari,Ankita;Werts,Miranda;Wong,AndrewR;Bailey,ConstanceB;Loubat,Arthur;Liu,Yuzhong;Chen,Yan;Chang,Samantha;Benites,VeronicaT;Her
聚酮合酶（PKS）工程是一种有吸引力的方法，以产生新的分子，如商品，精细和特种化学品。一个重大挑战是重新设计部分还原的PKS模块，以通过还原环（RL）交换产生饱和β-碳。在这项工作中，我们试图建立化学信息学，一个传统上用于药物发现的领域，为RL交换提供了一个可行的策略。我们首先将一组不同遗传来源和化学底物的供体RL引入脂霉素PKS的第一个延伸模块（LipPKS 1）中。这些工程化单模块PKS的产物滴度与供体RL和受体LipPKS 1的底物之间的化学结构相似性相关，达到由宿主Streptomyces albusJ 1074产生的165 mg/L的短链脂肪酸滴度。将这种方法扩展到需要双模通信的较大中间体，我们将不同化学相似性的RL引入LipPKS 2并确定三酮内酯的生产。总的来说，我们观察到原子对化学相似性和生产之间的统计学显著相关性，建立了一种新的化学信息学方法，可以帮助PKSs的工程设计，以产生所需的，非天然的产品。
Polyketide synthase (PKS) engineering is an attractive method to generate new molecules such as commodity, fine and specialty chemicals. A significant challenge is re-engineering a partially reductive PKS module to produce a saturated β-carbon through a reductive loop (RL) exchange. In this work, we sought to establish that chemoinformatics, a field traditionally used in drug discovery, offers a viable strategy for RL exchanges. We first introduced a set of donor RLs of diverse genetic origin and chemical substrates into the first extension module of the lipomycin PKS (LipPKS1). Product titers of these engineered unimodular PKSs correlated with chemical structure similarity between the substrate of the donor RLs and recipient LipPKS1, reaching a titer of 165 mg/L of short-chain fatty acids produced by the hostStreptomyces albusJ1074. Expanding this method to larger intermediates that require bimodular communication, we introduced RLs of divergent chemosimilarity into LipPKS2 and determined triketide lactone production. Collectively, we observed a statistically significant correlation between atom pair chemosimilarity and production, establishing a new chemoinformatic method that may aid in the engineering of PKSs to produce desired, unnatural products.