Taxol taxadiene synthase

HUANG, E. X., HUANG, Q. L WILDUNG, M. R CROTEAU, R SCOTT, A. I. Overproduction, in Escherichia coli, of soluble taxadiene synthase, a key enzyme in the taxol biosynthetic pathway, Protein Expression Purification, 1998,13,90-%. 

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. 

Wildung, M.R. and Croteau, R. (1996) A cDNA clone for taxadiene synthase, the diterpene cyclase that catalyzes the committed step of taxol biosynthesis. /. Biol. Chem., 271, 9201-4. 

Williams, D. C., Barroll, B. J., Jin, Q., Rithner, C. D., Lenger, S. R., Floss, H. G., Coates, R. M.,Williams, R. M., Croteau, R., Intramolecular proton transfer in the cyclization of geranylgeranyl diphosphate to the taxa diene precursor of taxol catalyzed by recombinant taxadiene synthase,... 

A precursor to taxol, an anticancer drug, has also been produced from glucose in E. coli. IPP and DMAPP react together to form geranylgeranyl diphosphate which is transformed to taxadiene by taxadiene synthase. Enzymes for some of these reactions were obtained from species in the Taxus genus of yews. A combinatorial approach was employed, in which expression of pathway enzymes was varied to achieve final concentrations of taxadiene over 1 gl , a 15000-fold improvement over the control strain [40]. 

Wildung MR, Croteau R (1996) A cDNA Clone for Taxadiene Synthase, the Diterpene Cyclase That Catalyzes the Committed Step of Taxol Biosynthesis. J Biol Chem 271 9201... 

Williams DC, Carroll BJ, Jin Q, Rithner CD, Lenger SR, Floss HG, Coates RM, Williams RM, Croteau R (2000) Intramolecular Proton Transfer in the Cyclization of Geranylgeranyl Diphosphate to the Taxadiene Precursor of Taxol Catalyzed by Recombinant Taxadiene Synthase. Chem Biol 7 969... 

The diterpene taxol from Pacific yew is one of the most powerful anticancer agents in therapeutic use today. In a series of seminal discoveries, the group of Croteau has dissected the pathway to this complex molecule at the enzymatic and molecular genetic levels, leading to recent success in partial reconstmction of the pathway in yeast [33]. The diterpene synthase taxadiene synthase catalyzes the cyclization of GGPP as the first committed step in taxol formation [34]. 

It uses a series of enzyme-controlled reactions. The step responsible for the creation of the unusual core is a cyclization reaction which changes geranylgeranyl diphosphate into taxa-4,11-diene. This then undergoes a variety of processes involving oxidation, acylation, and addition of a side chain to form taxol. The structure of the enzyme responsible for this, taxadiene synthase, was reported injanuary 2011. 

A series of ionization and proton-induced cycUzations 16 20 catalyzed by the taxadiene synthase convert GGPP 1 into the taxadienes 21 and 22 for en mute synthesis of biological important natural products such as taxol and analogs (Scheme 8.2) [7]. Abietanes andkauranes are important classes of diterpenes. In the presence of abietadiene synthase, 1 undergoes a proton-induced cascade cyclization to produce the copalyl diphosphate intermediate 23 (Scheme 8.2) [8]. The latter is converted to 24 via an ionic cyclization and then to 25 through a methyl 1,2-shift between C13 and C14 [9]. In contrast, diterpene mt-kaur-16-ene 29 is not formed via the same cyclase enzyme. Consequently, it was proposed that two enzymes, mt-copalyl diphosphate and cnt-kaurene... 

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