Sustainable biomanufacturing of paclitaxel: From pathway elucidation to green production systems

Paclitaxel remains irreplaceable in cancer therapy, yet its supply is critically constrained by the ecological unsustainability of plant extraction and the prohibitive costs of chemical synthesis. The recent and near-complete elucidation of its complex biosynthetic pathway in Taxus species has created a pivotal opportunity to transition toward sustainable microbial bioproduction. This review synthesizes the latest breakthroughs in the field, beginning with the comprehensive mapping of the paclitaxel biosynthetic network. This includes the recent discovery of key cytochrome P450 and 2-oxoglutarate/Fe(II)-dependent dioxygenase enzymes that resolve long standing questions regarding taxane core oxidation and oxetane ring formation. We critically evaluate the progress and inherent challenges in reconstructing this intricate pathway within heterologous chassis, including Escherichia coli, Saccharomyces cerevisiae and plant-based systems, highlighting bottlenecks related to P450 catalytic efficiency, metabolic burden and product cytotoxicity. Furthermore, this review explores emerging frontiers in synthetic biology, such as AI-driven enzyme engineering, the development of novel chassis like oleaginous yeast, the design of synthetic consortia and photosynthetic microalgae as promising platforms. By integrating fundamental pathway discovery with industrial application, this review provides insights for establishing a scalable, economically viable and environmentally sustainable supply of this essential agent.