The History of Studies on Oxetane Ring Formation in Paclitaxel Biosynthesis

There is no doubt that breakthroughs in the enzyme-mediated formation of the oxetane ring in paclitaxel biosynthesis constitute significant milestones in the biosynthesis of complex natural products. In this review, we summarize the understanding of the biosynthesis of the oxetane ring of paclitaxel from different viewpoints. Generally, it covers five aspects, (1) a different understanding of the mechanistic formation of the oxetane ring on the basis of sound chemical reasoning, (2) a reasonable speculation of the biosynthetic pathways and suitable surrogate substrates for oxetane ring formation based on the natural and chemical logical analysis, (3) Taxus genome-enabled enzymes identification, (4) the discovery of different enzymes that mediate oxetane ring formation, and (5) a mechanistic investigation involving the use of isotopic labelling experiments and quantum chemical calculations. This review provides a detailed overview of the history of the studies on the oxetane ring formation in paclitaxel biosynthesis, which may be useful for a better understanding this process in combined view of nature, chemistry and biology logics, also for efficient heterologous reconstruction of the paclitaxel biosynthetic pathway in the future.