Crystal Structure and Potential Head-to-Middle Condensation Function of a <i>Z</i>,<i>Z</i>‑Farnesyl Diphosphate Synthase

Plants produce a wide variety of secondary metabolites in response to adverse environmental factors. <i>Z</i>,<i>Z</i>-Farnesyl diphosphate (<i>Z</i>,<i>Z</i>-FPP), synthesized by <i>Z</i>,<i>Z</i>-farnesyl diphosphate synthase (<i>z</i>FPS), supports the formation of phytochemicals in wild tomatoes. Here, the crystal structure of N-terminal truncated <i>z</i>FPS (Δ<i>z</i>FPS) was determined. Irregular products including lavandulyl diphosphate and an unknown compound were surprisingly found. Apart from the truncated N-terminus as a functional regulator, structure-based analysis and mutagenesis assays revealed a residue H103 in Δ<i>z</i>FPS as one of the key elements to this irregular function. A series of substrate–enzyme complex structures were obtained from Δ<i>z</i>FPS-H103Y by co-crystallizing with isopentenyl diphosphate, dimethylallyl thiolodiphosphate, or both. Various substrate-binding modes were revealed. The catalytic mechanisms of both the head-to-tail and head-to-middle reactions in Δ<i>z</i>FPS were proposed. Functional switch between the two mechanisms in this enzyme and the essential role played by the flexible C-terminus were elucidated as well