Lasch Constanze, Myronovskyi Maksym, Luzhetskyy Andriy
Saarland University, Department of Pharmacy, Saarbrücken, Germany.
Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
Nat Prod Rep. 2025 Sep 9. doi: 10.1039/d5np00036j.
Focus on 2004 to 2024The rediscovery of natural products (NPs) as a critical source of new therapeutics has been greatly advanced by the development of heterologous expression platforms for biosynthetic gene clusters (BGCs). Among these, species have emerged as the most widely used and versatile chassis for expressing complex BGCs from diverse microbial origins. In this review, we provide a comprehensive analysis of over 450 peer-reviewed studies published between 2004 and 2024 that describe the heterologous expression of BGCs in hosts. We present a data-driven overview of expression trends across time, BGC types, donor species, and host strain preferences, offering the first quantitative perspective on how this field has evolved over two decades. Our review discusses the key factors influencing successful BGC expression in , including genomic integration strategies, regulatory elements, codon optimization, and precursor supply. We also examine the impact of synthetic biology tools, genome engineering, and host strain tailoring in overcoming common expression barriers. Special emphasis is placed on the role of heterologous expression in accessing silent or cryptic BGCs, elucidating biosynthetic pathways, and generating new-to-nature analogues through combinatorial biosynthesis. By integrating technological advances with practical case studies, we highlight how -based heterologous expression is enabling not only the efficient production of known compounds but also the discovery of structurally novel and biologically potent metabolites. This review aims to serve as a resource for researchers in natural products, synthetic biology, and drug discovery who seek to harness the full potential of microbial biosynthetic diversity.
聚焦2004年至2024年
天然产物（NPs）作为新疗法的关键来源的重新发现，因生物合成基因簇（BGCs）异源表达平台的发展而取得了巨大进展。其中，[具体物种]已成为表达来自不同微生物来源的复杂BGCs最广泛使用且通用的底盘。在本综述中，我们对2004年至2024年间发表的450多项同行评审研究进行了全面分析，这些研究描述了BGCs在[具体宿主]中的异源表达。我们提供了一个基于数据的关于不同时间、BGC类型、供体物种和宿主菌株偏好的表达趋势概述，首次从定量角度呈现了该领域在二十年间的发展情况。我们的综述讨论了影响[具体宿主]中BGCs成功表达的关键因素，包括基因组整合策略、调控元件、密码子优化和前体供应。我们还研究了合成生物学工具、基因组工程和宿主菌株定制在克服常见表达障碍方面的影响。特别强调了异源表达在获取沉默或隐秘BGCs、阐明生物合成途径以及通过组合生物合成产生新的天然类似物方面的作用。通过将技术进步与实际案例研究相结合，我们强调了基于[具体宿主]的异源表达如何不仅能够高效生产已知化合物，还能发现结构新颖且具有生物活性的代谢产物。本综述旨在为天然产物、合成生物学和药物发现领域中寻求充分利用微生物生物合成多样性潜力的研究人员提供参考资源。
