Farnesyl diphosphate synthase structures

Dunford, J.E., Thompson, K., Coxon, F.P., Luckman, S.P., Hahn, F.M., Poulter, C.D., Ebetino, F.H., and Rogers, M.J. (2001). Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296 235-242. 

The first step taken in the biosynthetic pathway of artemisinin was the cyclization of the general mevalonate pathway originated sesquiterpenoid precursor farnesyl diphosphate (FPP) into IS, 6R, 7R, i0it)-amorpha-4,ll-diene by amorpha-4,11-diene synthase (AMDS) (Fig. 4) [6-8]. The crystal structure of this sesquiterpene synthase is not known. From aU plant... 

A further element shared by all sesquiterpene synthases is the need for a divalent metal ion as cofactor. The metal ion is essential for substrate binding but also for product specificity. The metal ions stabihze the negatively charged pyrophosphate group of farnesyl diphosphate as illustrated by the crystal structure of 5-epz-aristolochene synthase [9]. The highly conserved sequence (I, L, V)DDxxD(E) serves to bind the metal ions in all known terpene and prenyl synthases (Fig. 5) [18-22]. A further interesting property among terpene synthases is that the active sites are enriched in relatively inert amino acids, thus it is the shape and dynamic of the active site that determines catalytic specificity [23]. 

FIGURE 7.4 Crystal structure of (a) bisabolene synthase active center bound to farnesyl diphosphate inhibitor (b) aristolochene synthase cocrystallized with FDP (metal coordination and hydrogen bonds are shown as dashed lines magnesium anions and water molecules are shown as spheres) and the proposed catalytic mechanisms for each cyclization Images created with PyMOL. (See insert for color representation of the figure.)... 

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