Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase.

Abstract

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.

1 Figure or Table

Statistics

050100150'03'05'07'09'11'13'15'17
Citations per Year

431 Citations

Semantic Scholar estimates that this publication has 431 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Montalvetti2001BisphosphonatesAP, title={Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase.}, author={Andrea Montalvetti and Brian N. Bailey and Michael B. Martin and Gregory Severin and Eric Oldfield and Roberto Docampo}, journal={The Journal of biological chemistry}, year={2001}, volume={276 36}, pages={33930-7} }