Taxanes biosynthesis

Laskaris, G., Van Der Heijden, R. and Verpoorte, R. (2000) Purification and partial characterisation of geranylgeranyl diphosphate synthase, from Taxus baccata cell cultures. An enzyme that regulates taxane biosynthesis. Plant Sci., 153, 97-105. 

Eisenreich, W., Menhard, B., Hylands, P.J. et al. (1996) Studies on the biosynthesis of Taxol the taxane carbon skeleton is not of mevalonoid origin. Proceedings of the National Academy of Sciences of the United States of America, 93, 6431-6436. 

Fig. 2. Schematic representation of paclitaxel biosynthesis. Dimethylallyl-diphosphate and isopentenyl-diphosphate are condensed through geranylgeranyl diphosphate synthase activity to render geranylgeranyl-diphosphate (GGPP). GGPP is converted into taxa-4(5), 11 (12)-diene in a reaction catalyzed by the taxane synthase (TS). A series of reactions catalyzed by cytochrome P450 monoxygenases lead to the production of a taxane intermediate that is further converted to baccatin III through enzymes-driven oxidation and oxetane ring formation. The side chain moiety of paclitaxel is derived from L-phenylalanine. Three consecutive arrows mean multiple steps. Ac, acetyl Bz, benzoyl.

The interdependence of methyl jasmonate with chitin- and chitosan-derived elicitors was studied using plant cell suspension cultures of Taxus canadensis. Induction of the biosynthesis of paditaxel and other taxanes was enhanced when methyl jasmonate and elicitors were added 8 days after culture transfer compared to treatments in which only methyl jasmonate or only elicitor was added. The optimal elicitor concentration using AT-acetylchitohexaose was 0.450 pM, but only in the presence of methyl jasmonate. Little, if any, induction of taxane formation occurred with the oligosaccharide alone. The optimal methyl jasmonate concentration was 200 pM using colloidal chitin or oligosaccharides of chitin and chitosan as elicitors. 

Kevin Walker, Rodney Croteau, Taxol biosynthesis Molecular clotring of a betrzoyl-CaA taxane 2alpha-0-benzoyltransferase cDNA from Taxus and functional expression in Escherichia coli. Proceedings of the National Academy of Sciences USA, 97 (2000), 13591-13596. 

Walker K, Croteau R (2000) Taxol Biosynthesis Molecular Cloning of a Benzoyl-CoA Taxane 2a-0-benzoyltransferase cDNA from Taxus and Functional Expression in Escherichia coli. PNAS 97 13591... 

It is now known that there are more than 380 kinds of natural taxane in Taxus. The biosynthesis of taxanes is generally believed to occur as follows. Farnesyl diphosphate (FPP) and isopentenyl pyrophosphate (IPP) are first catalyzed by GGPP synthase to produce geranylgeranyl-pyrophosphate (GGPP), and then taxa-4(5),ll(12)-diene is produced under the action of taxa-diene synthase. Next, taxanes are produced by the hydroxylase oxidation of the taxa-4(20),ll(12)-dien-5a-ol diterpene parent ring. The biosynthetic pathway for taxanes is illustrated in Figure 6.7. 

Jeimewein S, RithnerCD, Williams RM, Croteau RB (2001) Taxol biosynthesis taxane 13a-hydroxylase is a cytochrome P450-dependent monooxygenases. Proc Natl Acad Sci U S A 98 13595-13600... 

FIGURE 2.3 A simplified representation of the biosynthesis of Taxol . The first committed step is the cyclization of geranylgeranyl pyrophosphate to the taxane skeleton. A series of site- and enantio-selective hydroxylations then takes place, followed by further transformations. 

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