Structural analysis of farnesyl pyrophosphate synthase from parasitic protozoa, a potential chemotherapeutic target

Infect Disord Drug Targets. 2008 Mar;8(1):16-30. doi: 10.2174/187152608784139587.

Abstract

Synthesis of farnesyl pyrophosphate (FPP), a key intermediate of the isoprenoid biosynthesis pathway, is catalyzed by FPP synthase (FPPS). Antiprotozoal properties of bisphosphonates, which target FPPS, have generated interest in FPPS as a potential antiprotozoal drug target. The genes encoding FPPS from parasitic protozoa were assessed to analyze structural and functional features of the enzyme. Comparisons of the FPPS from the parasitic protozoa and search for conserved motifs revealed that FPPS from both apicomplexan and trypanosomatid parasites show characteristic conserved regions for example first aspartate rich motif (FARM) contained within II conserved domain and the second aspartate rich motif (SARM) contained within VI conserved domain. Phylogenetic analysis of FPPS generated a tree with three distinct clusters. Overall topology of the phylogenic tree constructed with small subunit ribosomal RNA sequences was almost similar to that constructed with FPPS sequences. Comparative homology modeling and structural comparisons of FPPS from the parasitic protozoa provided significant insights into common and distinct characteristics of the enzyme. The critical interacting residues of the isopentenyl pyrophosphate binding site are conserved across the enzymes from the family except for malarial FPPS where the C-terminal residues from the BXB motif of helix J were missing. Variations noticed in aromatic residue pairs at the fourth and fifth position upstream of the FARM, which play important role in determination of chain length of the polyprenyl products, may produce functional differences among protozoan FPPSs. The structural comparison of protozoan FPPS may be useful in designing common or selective FPPS inhibitors as potential broad spectrum or selective antiprotozoal agents.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antiprotozoal Agents / pharmacology*
  • Binding Sites
  • Drug Delivery Systems
  • Eukaryota / drug effects*
  • Eukaryota / metabolism
  • Geranyltranstransferase / drug effects*
  • Geranyltranstransferase / metabolism
  • Phylogeny
  • Polyisoprenyl Phosphates / metabolism
  • Protozoan Infections / drug therapy
  • Sesquiterpenes / metabolism

Substances

  • Antiprotozoal Agents
  • Polyisoprenyl Phosphates
  • Sesquiterpenes
  • farnesyl pyrophosphate
  • Geranyltranstransferase