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Crystal structure of aristolochene synthase in complex with 12,13-difluorofarnesyl diphosphate
Structural highlights
FunctionARIS_ASPTE Catalyzes the cyclization of trans,trans-farnesyl diphosphate (FPP) to the bicyclic sesquiterpene aristolochene. Produces germacrene A as an enzyme-bound intermediate that is not released by the enzyme, but is further cyclized to produce aristolochene. Aristolochene is the likely parent compound for a number of sesquiterpenoid toxins produced by filamentous fungi.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe universal sesquiterpene precursor, farnesyl diphosphate (FPP), is cyclized in an Mg(2+)-dependent reaction catalyzed by the tetrameric aristolochene synthase from Aspergillus terreus to form the bicyclic hydrocarbon aristolochene and a pyrophosphate anion (PP(i)) coproduct. The 2.1-A resolution crystal structure determined from crystals soaked with FPP reveals the binding of intact FPP to monomers A-C, and the binding of PP(i) and Mg(2+)(B) to monomer D. The 1.89-A resolution structure of the complex with 2-fluorofarnesyl diphosphate (2F-FPP) reveals 2F-FPP binding to all subunits of the tetramer, with Mg(2+)(B)accompanying the binding of this analogue only in monomer D. All monomers adopt open activesite conformations in these complexes, but slight structural changes in monomers C and D of each complex reflect the very initial stages of a conformational transition to the closed state. Finally, the 2.4-A resolution structure of the complex with 12,13-difluorofarnesyl diphosphate (DF-FPP) reveals the binding of intact DF-FPP to monomers A-C in the open conformation and the binding of PP(i), Mg(2+)(B), and Mg(2+)(C) to monomer D in a predominantly closed conformation. Taken together, these structures provide 12 independent "snapshots" of substrate or product complexes that suggest a possible sequence for metal ion binding and conformational changes required for catalysis. X-ray crystallographic studies of substrate binding to aristolochene synthase suggest a metal ion binding sequence for catalysis.,Shishova EY, Yu F, Miller DJ, Faraldos JA, Zhao Y, Coates RM, Allemann RK, Cane DE, Christianson DW J Biol Chem. 2008 May 30;283(22):15431-9. Epub 2008 Apr 2. PMID:18385128[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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