关键词: 放线菌, 聚酮, 菌种重构, 产量, 代谢工程, 合成生物学

Abstract:

Actinomycetes, enriched with an abundance of secondary metabolites, have emerged as a critical resource for drug discovery. These organisms predominantly harbor bioactive compounds such as polyketides, non-ribosomal peptides, aminoglycosides, and terpenes, with polyketides representing the most diverse class. Polyketides are divided into three major categories based on polyketide synthase: type I, type II, and type III. Among these, type I polyketides are the most widely distributed and abundant, with macrocyclic lactone compounds serving as the most archetypal representatives. Macrocyclic lactone compounds, frequently utilized as antibiotics, anti-cancer agents, immunosuppressants, and antiparasitic agents, hold immense biological significance. This review delves into the intricacies of the biosynthetic process of macrolides. A multifaceted optimization strategy for the actinomycete polyketides biosynthesis system is proposed, encompassing genome remodeling, regulatory pathway recombination, combinatorial metabolic engineering, and the derivation and diversification of polyketide structures. Initially, by knocking out competing gene clusters and superfluous genomic islands, augmenting the supply of precursors, and enhancing precursor supply and lipid stream processing, researchers can obtain genome-minimized and optimized industrial chassis. This is coupled with strategies such as promoter engineering, regulatory factor engineering, overexpression of rate-limiting enzyme genes, enhanced substrate transport and tolerance, targeted modification of key enzymes, rational design of polyketides, etc. Subsequently, the optimized chassis strains and biosynthetic gene clusters are integrated, supplemented with multi-omics strategies, fermentation process optimization, and guided by rapidly evolving fields of synthetic biology enabling technologies and artificial intelligence, to develop a high-quality, efficient polyketides biosynthesis system. These advancements offer robust technical support for the large-scale production of polyketides pharmaceuticals and their novel derivatives. By employing a multi-dimensional approach, integrating the latest advancements in synthetic biology enabling technologies, and adhering to strategies that are green, environmentally friendly, highly efficient, and sustainable, we can effectively optimize and enhance the production of polyketides in actinomycetes. This presents new possibilities for the development and production of future pharmaceuticals.

Key words: actinomycetes, polyketide, strain reconstruction, production, metabolic engineering, synthetic biology