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Prenyltransferases are involved in the biosynthesis of isoprenoids through the condensation of C5 -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 Tyr107 /His139 for GGPPS, Leu164 for HexPPS, and Phe132 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 C55 -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 IC50 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.
Another prenyltransferase called dehydrosqualene synthase (CrtM) from Staphylococcus aureus, uses the head-to-head condensation of two farnesyl diphosphate (FPP) molecules to produce the presqualene diphosphate C30 molecule, resembling the human squalene biosynthesis.Interestingly, the C30 - presqualene diphosphate is the precursor for the biosynthesis of staphyloxanthin, the golden carotenoid pigment which promotes resistance of the bacteria to reactive oxygen species and host neutrophil-based killing. CrtM, therefore, has been tested as the target to treat the hospital- and community-acquired infections produced by methicillin-resistant S. aureus (MRSA). Based on the structural similarity between CrtM and human squalene synthase (SQS), SQS inhibitors for cholesterol-lowering activity in humans also can be bound to CrtM through blocking the biosynthesis of staphyloxanthin in vitro (median inhibitory concentration ~100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model (3).