A synthetic biology roadmap for sustainable production of the plant-originated anti-cancer drug paclitaxel.

Paclitaxel, a clinically potent anticancer drug derived from Taxus species, faces persistent challenges in sustainable supply. Synthetic biology presents substantial opportunities for its de novo production, particularly with recent breakthroughs in elucidating its intricate biosynthetic pathways. However, its heterologous biosynthesis is significantly constrained by key bottlenecks, including pathway complexity, poor P450 expression, and inefficient metabolic flux. In this study, we explore how synthetic biology facilitates pathway decoding and reconstruction and propose strategies involving nonclassical chassis such as plant-associated cyanobacteria and filamentous fungi to enhance P450 compatibility. We also present a pragmatic framework for the rational application of state-of-the-art tools, including cell-free systems, synthetic microbial consortia, hybrid chemoenzymatic synthesis, and machine learning, to sustainably produce paclitaxel and other natural products.