CRYSTAL-STRUCTURE OF RECOMBINANT FARNESYL DIPHOSPHATE SYNTHASE AT 2.6-ANGSTROM RESOLUTION

The synthesis of farnesyl diphosphate (FPP), a key intermediate in the isoprenoid biosynthetic pathway required for the synthesis of cholest erol and in the formation of prenylated proteins, is catalyzed by the enzyme farnesyl diphosphate synthase (FPS). The crystal structure of a vian recombinant FPS, the first three-dimensional structure for any pr enyltransferase, was determined to 2.6-Angstrom resolution. The enzyme exhibits a novel fold composed entirely of a-helices joined by connec ting loops. The enzyme's most prominent structural feature is the arra ngement of 10 core helices around a large central cavity. Two aspartat e-rich sequences that are highly conserved among the isoprenyl diphosp hate synthase family of prenyltransferases, and are essential for enzy matic activity, were found on opposite walls of this cavity, with the aspartate side chains approximately 12 Angstrom apart and facing each other. The location and metal ion binding properties of these sequence s suggest that the conserved aspartate residues participate in substra te binding or catalysis.