From Plants to Microbes: Harnessing Enzyme Promiscuity for Natural Product Synthesis

Enzyme promiscuity has increasingly garnered significant attention in recent years, with a growing number of enzymes exhibiting this trait being progressively characterized. In plant systems, enzyme promiscuity critically underpins adaptive evolution, where evolutionary pressures drive environmental acclimatization and functional innovation. Conversely, in synthetic biology, this property exhibits a dual-edged nature: broad substrate promiscuity facilitates heterologous biosynthesis of natural products while enabling exploration of novel enzymatic functions and new natural product scaffolds. However, concomitant challenges─including byproduct accumulation, diminished target product purity, and reduced catalytic efficiency stemming from compromised specificity─impede industrial-scale natural product synthesis. Despite these limitations, this inherent enzymatic feature has driven synergistic advancements across biocatalysis, biosynthesis, and protein engineering. This review systematically dissects the manifestations of enzyme promiscuity in microbial natural product biosynthesis and critically evaluates contemporary strategies for alleviating enzyme promiscuity. Ultimately, it seeks to advance mechanistic understanding of enzyme promiscuity and establish a foundational framework for developing high-efficiency biosynthetic platforms.