Multiproduct terpene synthases TPS4-B73 and TPS5-Delprim from maize (Zea mays) catalyze the conversion of farnesyl diphosphate (FDP) and geranyl diphosphate (GDP) into a complex mixture of sesquiterpenes and monoterpenes, respectively. Various isotopic and geometric isomers of natural substrates like (2Z)-[2-2H]- and [2,4,4,9,9,9-2H6]-(GDP) and (2Z,6E)-[2-2H]- and [2,4,4,13,13,13-2H6]-(FDP) were synthesized analogous to presumptive reaction interme-diates. On incubation with labeled (2Z) substrates, TPS4 and TPS5 showed much lower kinetic isotope effects than the labeled (2E) substrates. Interestingly, the products arising from the deuterated (2Z)-precursors revealed a distinct preference for cyclic products and exhibited a enhanced turnover on comparison with natural (2E)-substrates. This increase in the efficiency due to (2Z) configuration emphasizes the rate limiting effect of the initial (2E) → (2Z) isomer¬ization step in the reaction cascade of the multiproduct terpene synthases. Apart from turnover advantages, these results suggest that substrate geometry can be used as a tool to optimize the biosynthetic reaction cascade towards valuable cyclic terpenoids.