4.1. Terpene indole alkaloids biosynthesis
The chief precursor in the synthesis of expensive anticancer drugs vinblastine and vincristine are strictosidine. This compound undergoes a series of reactions and forms compounds of diverse structure and biological function. Strictosidine is formed from the combination of tryptamine and secologanin, which are synthesized through the indole and mevalonate pathway, respectively. Firstly, in the TIA synthesis pathway, geraniol is formed from geranyl diphosphate (GDP) in the presence of geraniol synthase (GES). Later, geraniol is hydroxylated to 10-hydroxy-geraniol catalyzed by geraniol 10-hydroxylase, which has a regulatory role in the TIAs synthesis pathway. Following a series of steps, loganin is formed. In the last stage of the iridoid pathway, in the presence of secologanin synthase, loganin is converted into secologanin. On the other hand, a single enzymatic reaction comprises of conversion of L-tryptophan catalyzed by tryptophan decarboxylase yields tryptamine. Condensation of secologanin and tryptamine lead to the formation of strictosidine, a central intermediate of the TIAs pathway, by an enzyme strictosidine synthase. In the vindoline pathway, this compound undergoes a series of enzymatic reactions to produce catharanthine and vindoline, which includes two recently discovered enzymes dihydroprecondylocarpine synthase (PAS) and dehydrogenase dihydroprecondylocarpine synthase (DPAS) (Caputi et al., 2018) that converts an immediate stemmadenine acetate to tabsersonine and catharanthine. This reaction is catalyzed by vacuolar class III peroxidase to produce α3’, 4”anhydrovinblastine, which after several steps, converted into vinblastine and vincristine (Dutta et al., 2005; Zhou et al., 2010; Zhu et al., 2014) (Fig. 8 ).