TAXOL BIOSYNTHESIS - AN UPDATE

The novel diterpenoid taxol (paclitaxel) is now well-established as a potent chemotherapeutic agent. Total synthesis of the drug is not comm ercially feasible and, in the foreseeable future, the supply of taxol and its synthetically useful progenitors must rely on biological metho ds of production. The first three steps of taxol biosynthesis have bee n defined and the responsible enzymes described. These are the cycliza tion of the universal diterpenoid precursor geranylgeranyl diphosphate to taxa-4(5),11(12)-diene, the cytochrome P450-catalyzed hydroxylatio n of this olefin to taxa-4(20),11(12)-dien-5 alpha-ol, and the acetyl CoA-dependent conversion of the alcohol to the corresponding acetate e ster. Demonstration of these early steps of taxol biosynthesis suggest s that the complete pathway can be defined by a systematic, stepwise a pproach at the cell-free enzyme level. When combined with in vivo stud ies to determine contribution to pathway flux, slow steps can be targe ted for gene isolation and subsequent overexpression in Taxus to impro ve the yield of taxol and related compounds.