Alternative sources and metabolic engineering of Taxol: Advances and future perspectives.

Paclitaxel is one of the strong plant-derived anti-cancer drugs that was first isolated from the Pacific yew. Despite many paclitaxel's clinical successes, the limited accessibility of paclitaxel for clinical trials is recognized as the most important challenge. Thus, researchers are continuously trying to find the innovative ways to meet the community's need for this medicine. In the first step, the alternative sources for Taxol supply were recognized, such as Taxus genus, other plant genera, and endophytic fungi. In the next step, the biosynthetic pathways of Taxol or related metabolites were manipulated in the original organisms, or introduced to heterologous systems and then were manipulated in them. Here, a range of metabolic manipulating approaches have been successfully developed to redirect the metabolic flux toward Taxol, including promoter engineering, enzyme engineering, overexpressing the bottleneck enzymes, over- or down-regulation of transcription factors, activation of the cryptic genes, removing/minimizing the flux for competing pathways, tunable regulation of the metabolic pathway, and increasing the supplies of precursors. In this review, we discuss research progress on the alternative Taxol sources and its metabolic manipulating, and we suggest recent challenges and future perspectives.