Controlled Mutation to Make Drugs 

Proposed mechanism for diterpene synthases in the formation of phomactatriene and taxadiene

Tetsuo Tokiwano, Taeko Endo, Tae Tsukagoshi, Hitoshi Goto, Eri Fukushi and Hideaki Oikawa   

Key reactions in the biosynthesis of the medicinally important compounds phomactin and taxol were investigated by Hideaki Oikawa and colleagues at Hokkaido University, Japan.   Cyclizations of a linear polyene precursor with the corresponding cyclases create complex skeletons, phomactan and taxane, via a common carbocationic intermediate. The fate of this key intermediate was investigated by acid-catalyzed non-enzymatic reactions and molecular orbital calculations. 

Oikawa et al. showed that the supposed phomactriene synthase produces phomactriene along with minor diterpene hydrocarbons which are formed via alternative cyclizations. This indicates that minute changes in the active site of this enzyme may result in production of structurally related products. Thus, controlled mutation of phomactriene synthase gene may convert the phomactriene synthase into the taxadiene synthase.