Synthetic biology for heterologous expression and engineering of fungal polyketide synthases

Covering: up to 2025Polyketide synthases (PKSs) are essential enzymatic systems that produce a wide range of natural products. Their biosynthetic features offer significant opportunities to create a broad range of polyketides for pharmaceutical, agricultural, and biotechnology applications. In this highlight article, we provide a brief overview of key aspects of PKS biosynthesis, their classification in bacteria and fungi, and the evolutionary mechanisms driving their diversification. After outlining the fundamentals of PKSs, we discuss two key design principles for fungal PKS engineering: host selection and engineering strategies. For host selection, we revisit the state of the art in heterologous expression in yeast and filamentous fungi. We then explore strategies for modifying fungal PKS activity through starter unit selection, point mutations, and domain swaps. Finally, we offer perspectives on future directions for fungal PKS engineering, highlighting the importance of exploring new hosts and integrating advanced computational tools.