Cytochrome P450 taxadiene 5α-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of taxol biosynthesis

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Abstract

The first oxygenation step in the biosynthesis of the anticancer drug taxol in Taxus species is the cytochrome P450-mediated hydroxylation (with double bond migration) of the diterpene olefin precursor taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5α-ol. A homology-based cloning strategy, employing an induced Taxus cell library, yielded a cDNA encoding taxadiene 5α-hydroxylase, which was functionally expressed in yeast and insect cells. The recombinant enzyme was characterized and shown to efficiently utilize both taxa-4(5),11(12)-diene and taxa-4(20),11(12)-diene (as an adventitious substrate) to synthesize taxa-4(20),11(12)-dien-5α-ol. This hydroxylase resembles, in sequence and properties, other cytochrome P450 oxygenases of taxol biosynthesis. The utilization of both taxadiene isomers in the formation of taxa-4(20),11(12)-dien-5α-ol is novel, suggesting a reaction mechanism involving promiscuous radical abstraction with selective oxygen insertion rather than epoxidation of the C4,C5-alkene of the natural substrate and allylic rearrangement of the resulting taxa-11(12)-en-4,5epoxide.

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Jennewein, S., Long, R. M., Williams, R. M., & Croteau, R. (2004). Cytochrome P450 taxadiene 5α-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of taxol biosynthesis. Chemistry and Biology, 11(3), 379–387. https://doi.org/10.1016/j.chembiol.2004.02.022

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