研究人员表示，细菌多模块聚酮合成酶（PKS）是一种巨型酶，可生成多种具有重要治疗作用但合成上具有挑战性的天然产物。通过对这些酶进行工程改造，可以实现聚酮结构的多样化。然而，尽管在顺式乙酰转移酶（顺式AT）PKS方面取得了成功，但定制这种大型装配线仍然具有挑战性。与教科书上的PKS不同，反式-AT PKS具有PKS模块的非凡多样性，并且通常会演化形成混合PKS。
研究人员分析了氨基酸的共同演化，以确定产生功能性PKS的共同模块位点。研究人员利用这个位点插入和删除了不同的PKS部分，并在两种细菌生产者中创建了22个来自不同途径的工程化反式AT PKS。这个工程方法成功率很高，这凸显了它在生成复杂的设计型聚酮类化合物方面的广泛适用性。
附：英文原文
Title: Evolution-guided engineering of trans-acyltransferase polyketide synthases
Author: Mathijs F. J. Mabesoone, Stefan Leopold-Messer, Hannah A. Minas, Clara Chepkirui, Pornsuda Chawengrum, Silke Reiter, Roy A. Meoded, Sarah Wolf, Ferdinand Genz, Nancy Magnus, Birgit Piechulla, Allison S. Walker, Jrn Piel
Issue&Volume: 2024-03-22
Abstract: Bacterial multimodular polyketide synthases (PKSs) are giant enzymes that generate a wide range of therapeutically important but synthetically challenging natural products. Diversification of polyketide structures can be achieved by engineering these enzymes. However, notwithstanding successes made with textbook cis-acyltransferase (cis-AT) PKSs, tailoring such large assembly lines remains challenging. Unlike textbook PKSs, trans-AT PKSs feature an extraordinary diversity of PKS modules and commonly evolve to form hybrid PKSs. In this study, we analyzed amino acid coevolution to identify a common module site that yields functional PKSs. We used this site to insert and delete diverse PKS parts and create 22 engineered trans-AT PKSs from various pathways and in two bacterial producers. The high success rates of our engineering approach highlight the broader applicability to generate complex designer polyketides.
DOI: adj7621
Source: https://www.science.org/doi/10.1126/science.adj7621