Bisphosphonates Are Potent Inhibitors of Trypanosoma cruzi Farnesyl Pyrophosphate Synthase

Andrea Montalvetti, Brian N. Bailey, Michael B. Martin, Gregory W. Severin, Eric Oldfield, Roberto Docampo

Research output: Contribution to journalJournal articleResearchpeer-review


We report the cloning and sequencing of a gene encoding the farnesyl pyrophosphate synthase of Trypanosoma cruzi. The protein (T. cruzi farnesyl pyrophosphate synthase, TcFPPS) is an attractive target for drug development, since the growth of T. cruzi is inhibited by carbocation transition state/reactive intermediate analogs of its substrates, the nitrogen-containing bisphosphonates currently in use in bone resorption therapy. The protein predicted from the nucleotide sequence of the gene has 362 amino acids and a molecular mass of 41.2 kDa. Several sequence motifs found in other FPPSs are present in TcFPPS. Heterologous expression of TcFPPS in Escherichia coli produced a functional enzyme that was inhibited by the nitrogen-containing bisphosphonates alendronate, pamidronate, homorisedronate, and risedronate but was less sensitive to the non-nitrogen-containing bisphosphonate etidronate, which, unlike the nitrogen-containing bisphosphonates, does not affect parasite growth. The protein contains a unique 11-mer insertion located near the active site, together with other sequence differences that may facilitate the development of novel anti-Chagasic agents.
Original languageEnglish
JournalJournal of Biological Chemistry
Issue number36
Pages (from-to)33930-33937
Number of pages8
Publication statusPublished - 2001
Externally publishedYes


  • Biochemistry
  • Agriculture, Biology and Environmental Sciences
  • Engineering and Technology
  • Life Sciences
  • Cloning
  • Genes
  • Nitrogen
  • Phosphorus compounds
  • Proteins
  • Molecular mass
  • alendronic acid
  • bisphosphonic acid derivative
  • etidronic acid
  • farnesyl diphosphate
  • geranyltransferase
  • pamidronic acid
  • risedronic acid
  • amino acid
  • calcium channel blocking agent
  • cation
  • drug derivative
  • geranyl pyrophosphate
  • isoprenoid phosphate
  • recombinant protein
  • transferase
  • apoptosis
  • article
  • drug potency
  • enzyme active site
  • enzyme inhibition
  • gene insertion
  • gene isolation
  • gene sequence
  • growth inhibition
  • molecular cloning
  • nonhuman
  • nucleotide sequence
  • priority journal
  • protozoal infection
  • Trypanosoma cruzi
  • amino acid sequence
  • animal
  • binding site
  • bird
  • cell culture
  • chemical model
  • chemical structure
  • chemistry
  • DNA sequence
  • dose response
  • drug antagonism
  • enzymology
  • Escherichia coli
  • genetics
  • metabolism
  • molecular genetics
  • Northern blotting
  • pH
  • protein binding
  • protein motif
  • sequence homology
  • Southern blotting
  • X ray crystallography
  • insertion sequences
  • other sequences
  • Protozoa
  • Trypanosoma
  • Alkyl and Aryl Transferases
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acids
  • Animals
  • Binding Sites
  • Birds
  • Blotting, Northern
  • Blotting, Southern
  • Calcium Channel Blockers
  • Cations
  • Cells, Cultured
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Diphosphonates
  • Dose-Response Relationship, Drug
  • Etidronic Acid
  • Geranyltranstransferase
  • Hydrogen-Ion Concentration
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Polyisoprenyl Phosphates
  • Protein Binding
  • Recombinant Proteins
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid


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