A cytochrome P450-mediated intramolecular carbon-carbon ring closure in the biosynthesis of multidrug resistance-reversing lathyrane diterpenoids

The Euphorbiaceae produce a wide variety of bioactive diterpenoids. These include the lathyranes, which have received much interest due to their ability to inhibit the ABC transporters responsible for the loss of efficacy of many chemotherapy drugs. The lathyranes are also intermediates in the biosynthesis of range of other bioactive diterpenoids with potential applications in the treatment of pain, HIV and cancer. We report a gene cluster from Jatropha curcas containing the genes required to convert geranylgeranyl pyrophosphate into a number of diterpenoids including the lathyranes jolkinol C and epi-jolkinol C. The conversion of casbene to the lathyranes involves an intramolecular carbon-carbon ring closure. This requires the activity of two cytochrome P450s which we propose form a 6-hydroxy-5,9-diketo-casbene intermediate which then undergoes an aldol reaction. The discovery of the P450 genes required to convert casbene to lathyranes will allow the scalable heterologous production of these potential anti-cancer drugs, which can often only be sourced in limited quantities from their native plant.