Chemistry Reference
In-Depth Information
Figure 5.5
Pathway of Taxol biosynthesis in
Taxus
spp.
name rather than the generic name paclitaxel. The total synthesis of Taxol is pos-
sible (38), but it is not economically feasible currently because of the challenges
of stereochemistry, low yield, and high cost. The study of Taxol by Croteau
et al. (17) is an exceptional example of how a terpenoid biosynthetic pathway
was rationalized, and the synthesis and testing of various hypothetical precursors
with cell-free extracts have yielded the discovery of many enzymes and genes in
this complex pathway. Because Taxol is only found at very low levels in slow
growing trees, and is one of hundreds of Taxol-like compounds produced in a
metabolic grid, the use of an inducible
Taxus
cell culture system has accelerated
this research.
Taxol is biosynthesized in 19 steps from GGPP that originates from precur-
sors of the MEP pathway (Fig. 5.5). The biosynthesis of Taxol begins with the
formation of the tricyclic diterpene skeleton of taxa-4(5),11(12)-diene (17, 39).
All genes for the enzymes in this early pathway have been identified in
Taxus
cuspidata
and a taxa-4(5),11(12)-diene synthase has been identified in several
Taxus
species. The mechanism of this di-TPS has been explored in detail (39).
Taxa-4(5),11(12)-diene is then hydroxylated by several cytochrome P450 taxoid
oxygenases to yield a putative intermediate decorated with seven alcohol or ester
groups. Many cytochrome P450 enzymes that catalyze these transformations have
been identified and characterized, but two enzymes remain uncharacterized (17).
The biosyntheses of the ester functionalities have been studied, and several acyl
and aroyl transferases have been identified and characterized. Finally, studies on
the steps in the aromatic side chain assembly and attachment has yielded several
enzymes that include a phenylalanine aminomutase, a C13-phenylpropanoyl-CoA
transferase, and an
N
-benzoyl transferase. Although the pathway of biosynthesis
