Paclitaxel biosynthesis

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.

Experiments were conducted in which the gas mixture flowing to the culture flask contained MJ as well as ethylene [in the optimum combination with 17% (v/v) 02 and 1.5 % (v/v) C02]. The results given in Fig. 7 demonstrate clearly that ethylene and MJ co-mediate the induction of paclitaxel biosynthesis. When MJ was supplied by passing an air stream over concentrated MJ in a flask, no product formation was noted. When the optimal gas mixture was applied to the headspace of the culture without first passing over the pure MJ in a flask, the level of paclitaxel accumulation was about 20% of that found in the culture to which both MJ and C2H4 had been applied by means of the vapor phase. The 8-day period of time before induction may represent the time required for the critical concentration of MJ to dissolve in the culture medium under the flow (40 ml total gas mixture min-1) and temperature (21 °C) conditions of the experiment. 

A major advantage of the natural products approach to drug discovery is that it is capable of providing complex molecules that would not be accessible by other routes. Compounds such as paclitaxel (Taxol, 8) or rapamycin (10) would never be prepared by standard "medicinal chemistry" approaches to drug discovery, even including the newer methods of combinatorial chemistry. Likewise, the new approach of combinatorial biosynthesis, although an important one, is unlikely in the near future to yield new compounds of the complexity of paclitaxel and camptothecin. 

WILLIAMS, D. C., WILDUNG, M. R., JIN, A. Q. W., DALAL, D., OLIVER, J. S., COATES, R. M., CROTEAU, R., Heterologous expression and characterization of a "pseudomature" form of taxadiene synthase involved in paclitaxel (Taxol) biosynthesis and evaluation of a potential intermediate and inhibitors of the multistep diterpene cyclization reaction, Arch. Biochem. Biophys., 2000, 379, 137-146. 

A more efficient process to paclitaxel involves fermentation [69-71]. The biosynthesis starts from isoprenyl diphosphate and farnesyl diphosphate (Scheme 8.17). To achieve a high titer of paclitaxel production, cell cultures from various species of Taxus were investigated. For example, methyl jasmonate was able to enhance paclitaxel production to 55 mg I 1 per week in a cell suspension culture. The plant... 

Figure 1 Bulk drugs from natural sources Paclitaxel (antileukemic and antitumor) and lovastatin (inhibitor of cholesterol biosynthesis) are examples of the diverse and complex structures made by plant and microbial cell biosyntheses, respectively. In most instances of such compounds having desirable biological activities, their structural and chiral complexities make chemical synthesis not competitive with isolation from biosynthesis.

Engels, B., Dahmb, P. and Jennewein, S. (2008) Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production. Metabolic Engineering. 10, 201-206. 

Inorganic metal salts can induce secondary metabolism in plant cell cultures, such as Cu and Ag. Cu elicited phytoalexin production in rice plants. Adding AgNOs induced taxol biosynthesis. Rare earth metal salts, such as (NH4)2Ce(N03)6, can also increase the accumulation of paclitaxel in Taxus cells. Ginsenoside biosynthesis was elicited in cell cultures of Panax ginseng by vanadate. The metabolic action of inorganic metal salts inducing the accumulation of secondary metabolites may be similar to other natural chemical elicitors. ... 

Unnatural elicitors in the form of BTH derivatives and INA derivatives were aiso successfully applied in Taxus cells (Tables 6.6 and 6.7). The results showed that the biosynthesis of some secondary metabolites is regulated by some small compounds. The chemical bioengineering strategy lays the foundation not only for the industrial application of paclitaxel, but also for other bioprocess systems. 

Paclitaxel, commonly known as Taxol (the registered trademark), is a powerful diterpenoid anticancer dmg with an annual market value of several billion dollars [15]. Taxol was first isolated and identified from the bark of Pacific yew, a slow-growing tree that is adapted to a forest shade environment in the Pacific Northwest of North America. Pathway of the biosynthesis of Taxol in Taxus has been primarily deciphered as in Fig. 88.6. 

Biosynthesis Clinical trial Docetaxel Paclitaxel Taxoids Toxicology... 

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