Traditionally engineered to produce novel bioactive molecules, Type I modular polyketide synthases (PKSs) could be engineered as a new biosynthetic platform for the production of de novo fuels, commodity chemicals, and specialty chemicals. Previously, our investigations manipulated the first module of the lipomycin PKS to produce short chain ketones, 3-hydroxy acids, and saturated, branched carboxylic acids. Building upon this work, we have expanded to multi-modular systems by engineering the first two modules of lipomycin to generate unnatural polyketides as potential biofuels and specialty chemicals in Streptomyces albus. First, we produce 20.6 mg/L of the ethyl ketone, 4,6 dimethylheptanone through a reductive loop exchange in LipPKS1 and a ketoreductase knockouts in LipPKS2. We then show that an AT swap in LipPKS1 and a reductive loop exchange in LipPKS2 can produce the potential fragrance 3-isopropyl-6-methyltetrahydropyranone. Highlighting the challenge of maintaining product fidelity, in both bimodular systems we observed side products from premature hydrolysis in the engineered first module and stalled dehydration in reductive loop exchanges. Collectively, our work expands the biological design space and moves the field closer to the production of designer biomolecules.

中文翻译：

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双模块PKS平台扩展了生物学设计空间

I型模块化聚酮化合物合酶（PKS）传统上被设计用来生产新型生物活性分子，可以被设计成用于生产从头燃料，商品化学品和特种化学品的新型生物合成平台。以前，我们的研究操纵了脂霉素PKS的第一个模块来生产短链酮，3-羟基酸和饱和的支链羧酸。在这项工作的基础上，我们通过设计脂霉素的前两个模块，将其扩展到多模块系统，以产生不天然的聚酮化合物，作为潜在的生物链霉菌中的生物燃料和特种化学品。首先，我们通过LipPKS1中的还原环交换和LipPKS2中的酮还原酶敲除产生20.6 mg / L的乙基酮，4,6二甲基庚酮。然后，我们表明，LipPKS1中的AT交换和LipPKS2中的还原性环交换可以产生潜在的芳香剂3-异丙基-6-甲基四氢吡喃酮。突出了维持产品保真度的挑战，在两个双模块系统中，我们都观察到了副产物，这些副产物来自工程化的第一个模块中的过早水解和还原性回路交换中失速的脱水。总的来说，我们的工作扩大了生物设计的空间，并使该领域更接近于设计生物分子的生产。