Department of Chemical and Biological Engineering, Korea University, Seoul, Republic of Korea.
Biotechnol Bioeng. 2023 Jul;120(7):2039-2044. doi: 10.1002/bit.28400. Epub 2023 Apr 12.
Streptomyces are important industrial bacteria that produce pharmaceutically valuable polyketides. However, mass production on an industrial scale is limited by low productivity, which can be overcome through metabolic engineering and the synthetic biology of the host strain. Recently, the introduction of an auto-inducible expression system depending on microbial physiological state has been suggested as an important tool for the industrial-scale production of polyketides. In this study, titer improvement by enhancing the pool of CoA-derived precursors required for polyketide production was driven in a quorum sensing (QS)-dependent manner. A self-sustaining and inducer-independent regulatory system, named the QS-based metabolic engineering of precursor pool (QMP) system, was constructed, wherein the expression of genes involved in precursor biosynthesis was regulated by the QS-responsive promoter, scbAp. The QMP system was applied for neoaureothin production in a heterologous host, Streptomyces coelicolor M1152, and productivity increased by up to 4-fold. In particular, the engineered hyperproducers produced high levels of neoaureothin without adversely affecting cell growth. Overall, this study showed that self-regulated metabolic engineering mediated by QS has the potential to engineer strains for polyketide titer improvement.
链霉菌是产生具有药用价值的聚酮类化合物的重要工业细菌。然而，由于生产力低，大规模工业化生产受到限制，这可以通过代谢工程和宿主菌株的合成生物学来克服。最近，人们提出了一种依赖微生物生理状态的自动诱导表达系统，作为聚酮类化合物工业生产的重要工具。在这项研究中，通过增强聚酮类化合物生产所需的 CoA 衍生前体库来提高效价，这是一种依赖于群体感应 (QS) 的方式。构建了一种自维持且不依赖诱导剂的调控系统，命名为基于 QS 的前体库代谢工程 (QMP) 系统，其中涉及前体生物合成的基因的表达受 QS 响应启动子 scbAp 调控。将 QMP 系统应用于异源宿主变绿链霉菌 M1152 中的尼奥 Aureothin 生产，效价提高了 4 倍。特别是，经过工程改造的超生产菌在不影响细胞生长的情况下产生了高水平的尼奥 Aureothin。总的来说，这项研究表明，由 QS 介导的自我调控代谢工程有可能用于聚酮类化合物效价的提高。
