Stu Borman

Four research groups, working collaboratively, have determined the remarkable single-step mechanism by which the acyclic compound geranylgeranyl diphosphate (GGPP) is converted biosynthetically into the tricyclic core of Bristol-Myers Squibb's anticancer agent Taxol (paclitaxel). The work has implications for the development of improved processes for producing Taxol and other terpenoids biosynthesized by similar cyclization mechanisms.

In the cascade reaction that leads to the tricyclic Taxol core structure, the researchers have discovered what appears to be the first intramolecular proton transfer that is not enzyme-assisted. Such proton transfers are generally believed to be assisted by enzyme active-site bases, but in Taxol biosynthesis a double bond in the substrate seems to act as a "base" by accepting the proton.

The study was a collaboration by chemistry professor Heinz G. Floss of the University of Washington; chemistry professor Robert M. Coates of the University of Illinois, Urbana-Champaign; chemistry professor Robert M. Williams of Colorado State University, Fort Collins; professor of biological chemistry Rodney Croteau of Washington State University, Pullman; and their coworkers [Chem. Biol., 7, 969 (2000)].

The initiating reaction in the biosynthesis of Taxol in yew trees such as Taxus brevifolia is the single-step conversion of GGPP into a diterpene hydrocarbon, taxa-4(5),11(12)-diene. Three stereogenic centers and all three interconnected rings are formed in the reaction.

Using mass spectrometric and nuclear magnetic resonance (NMR) analysis, Floss, Coates, Williams, Croteau, and coworkers have now determined the reaction's mechanism of cyclization. The process begins with dissociation of diphosphate and closure of two rings. This is followed by the unique unassisted intramolecular proton transfer, a cyclization to form the third ring, and a proton elimination.

The work "is a beautiful example of a collaboration involving groups with expertise in organic synthesis, enzymology, molecular biology, and NMR analysis to solve a tough stereochemical problem," says chemistry professor C. Dale Poulter of the University of Utah, whose research interests include mechanisms of enzyme-catalyzed reactions.

The study indicates "that the cascade of events required to convert GGPP to taxadiene is set up by the precise conformation of the substrate in the catalytic site of the enzyme and that the absolute stereochemical fidelity of the transformation is a consequence of conformational control," Poulter continues. "Also, the intramolecular proton transfer in taxadiene synthesis appears to not require assistance by the enzyme--beyond setting the conformation of the substrate before initiating the reaction." This is unusual, he affirms.

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