Protonation-Triggered Carbon-Chain Elongation in Geranyl Pyrophosphate Synthase (GPPS)

Geranyl pyrophosphate synthase (GPPS) is responsible for the formation of geranyl pyrophosphate (GPP), a key intermediate which has the potential to derive numerous functionally and structurally diverse groups of terpenoid natural products via the head-to-tail assembly of two isoprenoid building blocks (dimethylallyl diphosphate, DMAPP; isopentenyl diphosphate, IPP) in the initial step of carbon-chain elongation during isoprenoid biosynthesis. Elucidating the detailed catalytic mechanism in GPPS is of significant interests as it will stimulate the development of new technology in generating novel natural productlike scaffolds. It has been known that the catalytic reaction involves three sequential steps, namely “ionization–condensation–elimination”, but the exact catalytic mechanism has remained controversial since the 1970s. By employing Born–Oppenheimer density functional quantum mechanics (B3LYP/6-31(+)G*)/molecular mechanics dynamics simulations, here we suggest that GPPS adopts a protonation-induced ...