Paclitaxel biosynthesis: the early steps.
Croteau R. | Hezari M. | Hefner J. | Koepp A. | Lewis N.G.
The biosynthesis of taxol and related taxoids in yew (Taxus) species is thought to involve the cyclization of the common isoprenoid intermediate geranylgeranyl diphosphate to a taxadiene followed by extensive, largely oxidative, modification of this diterpene olefin precursor. This sequence of reactions leading to taxol likely requires in excess of a dozen distinct enzymatic steps, exclusive of the construction of the N-benzoyl phenylisoserine side chain moiety, which has been shown by H.G. Floss and his colleagues to originate from phenylalanine and to involve esterification at C13 of the very advanced intermediate baccatin III. No early steps of the pathway have been defined and none of the enzymes involved in taxol biosynthesis have been described until quite recently. A cell-free extract of yew saplings was shown to catalyze the conversion of [1-3H] geranylgeranyl diphosphate to a cyclic diterpene olefin that was identified as taxadiene by spectroscopic means and was demonstrated to serve as a precursor of taxoids in vivo. The cyclization enzyme that catalyzes this first committed step of taxol biosynthesis is described, as are preliminary studies on the initial oxygenation of taxadiene catalyzed by a presumptive cytochrome P450 hydroxylase. Demonstration of the first two specific enzymatic steps of taxol biosynthesis suggests that the complete pathway can be defined by a systematic, stepwise approach at the cell-free enzyme level.
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