Prenyltransferases as Targets for the Discovery of New Antibiotics

Abstract

Prenyltransferases are involved in the biosynthesis of isoprenoids through the condensation of C 5 -diphosphates to form the compounds used in cell membrane, cell wall, terpene biosynthesis, electron transfer, and in many eukaryotes, cell signaling pathways (Ras, Rho, Rap, Rac). Therefore, there has been considerable interest in developing specific inhibitors as new drugs for various diseases associated with these pathways. Through our structural analysis efforts, we have studied the product chain length determinants of several trans-type prenyltransferases, including geranylgeranyl pyrophosphate synthase (GGPPS), hexaprenyl pyrophosphate synthase (HexPPS), and octaprenyl pyrophosphate synthase (OPPS). The specificities were determined by the size and depth of the activity site cavity. Large amino acids, such as Tyr 107 /His 139 for GGPPS, Leu 164 for HexPPS, and Phe 132 for OPPS, form the floor to block product further elongation (1). In addition, we solved the structures of yeast GGPPS complexed with several bisphosphonate inhibitors (2). Undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase, produces mixed (E,Z) long-chain C 55 -undecaprenyl diphosphate (UPP) via cis double-bond addition. It has been considered as a new target for anti-microbial therapy because UPP is used to form the lipid-I and lipid-II species needed for peptidoglycan cell-wall biosynthesis in bacteria. Here, bisphosphonates were tested as inhibitors of UPPS, with the most active one having an IC 50 of < 600 nM . In the UPPS-inhibitor complexes, four distinct binding sites were observed (2), in contrast to the observation of only one bisphosphonate-binding site in farnesyl diphosphate synthase (FPPS). The availability of these structures opens up new avenues for the design of novel inhibitors.