Between scents and sterols: Cyclization of labdane-related diterpenes as model systems for enzymatic control of carbocation cascades

The citrus scent arises from the volatile monoterpene limonene, whose cyclic nature can be viewed as a miniaturized form of the polycyclic sterol triterpenoids. In particular, these rings are all formed from poly-isoprenyl precursors via carbocation cascades. However, the relevant reactions are initiated by distinct mechanisms, either lysis/ionization of an allylic diphosphate ester bond, as in limonene synthases, or protonation of a terminal olefin or epoxide, as in lanosterol synthases. Labdane-related diterpenoids are unique in their utilization of both types of reactions. With over 7000 such natural products known, this pair of reactions clearly generates privileged scaffolds, hydrocarbon backbones from which biological activity is readily derived. Moreover, the relevant enzymes serve as model systems for terpene cyclization more generally. Indeed, investigation of their enzymatic structure-function relationships has highlighted the importance of catalytic base positioning within the active site cavity in specifying product outcomes. Conversely, comparison to the cyclases for other types of terpenoid natural products suggests new directions for discovery and/or engineering of the catalytic activity of those from labdane-related diterpenoid biosynthesis.