Figure 2:

(A) Catalytic mechanisms of wild-type EIZS and F96(S,M,Q) EIZS variants. Catalysis is initiated by ionization and isomerization of farnesyl diphosphate (OPP = diphosphate) to form (3R)-nerolidyl diphosphate, the cisoid conformer of which then undergoes re-ionization and cyclization to generate the (4R)-bisabolyl cation. A 1,2-hydride shift leads to the (7S)-homobisabolyl cation, which serves as a branch point for wild-type and F96X variants. Spirocyclization of the compressed conformation of the (7S)-homobisabolyl cation leads to formation of the (1S,4R,5R)-acorenyl cation in wild-type EIZS (blue curved arrows). The acorenyl cation then undergoes further cyclization, ring contraction, 1,2-methyl migration, and deprotonation to yield epi-isozizaene (blue curved arrows). In the F96X variants, an extended conformation of the (7S)-homobisabolyl cation intermediate yields a strained [3.1.0] bridged bicyclic cation, deprotonation of which yields sesquisabinene A (red curved arrows). (B) Molecular structures of ligands studied in EIZS complexes reported in this work.