Squalene synthase catalyzes the first committed step in cholesterol synthesis, mediating the reductive dimerization of farnesyl pyrophosphate to produce squalene. Zaragozic acid A is a fungal metabolite that acts as a reversible competitive inhibitor of squalene synthase (Ki = 78 pM in vitro). It dose-dependently reduces cholesterol synthesis in HepG2 cells (IC50 = 6 μM) and inhibits hepatic cholesterol synthesis in mice (ED50 = 0.2 mg/kg). Zaragozic acid A also inhibits farnesyl-protein transferase and geranylgeranyl-protein transferase type I (IC50s = 216 and 50 nM, respectively).
