skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer

Abstract

Bisphosphonates (BPs) are a class of compounds that have been used extensively in the treatment of osteoporosis and malignancy-related hypercalcemia. Some of these compounds act through inhibition of farnesyl diphosphate synthase (FPPS), a key enzyme in the synthesis of isoprenoids. Recently, nitrogen-containing bisphosphonates (N-BPs) used in bone resorption therapy have been shown to be active against Trypanosoma cruzi, the parasite that causes American trypanosomiasis (Chagas disease), suggesting that they may be used as anti-trypanosomal agents. The crystal structures of TcFPPS in complex with substrate (isopentenyl diphosphate, IPP) and five N-BP inhibitors show that the C-1 hydroxyl and the nitrogen-containing groups of the inhibitors alter the binding of IPP and the conformation of two TcFPPS residues, Tyr94 and Gln167. Isothermal titration calorimetry experiments suggest that binding of the first N-BPs to the homodimeric TcFPPS changes the binding properties of the second site. This mechanism of binding of N-BPs to TcFPPS is different to that reported for the binding of the same compounds to human FPPS.

Authors:
; ; ;  [1]
  1. UIUC
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002858
Resource Type:
Journal Article
Journal Name:
Proteins
Additional Journal Information:
Journal Volume: 78; Journal Issue: (4) ; 03, 2010; Journal ID: ISSN 0887-3585
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; CALORIMETRY; CRYSTAL STRUCTURE; ENZYMES; OSTEOPOROSIS; PARASITES; RESIDUES; SUBSTRATES; SYNTHESIS; THERAPY; TITRATION; TRYPANOSOMA; TRYPANOSOMIASIS

Citation Formats

Huang, Chuan-Hsiang, Gabelli, Sandra B, Oldfield, Eric, Amzel, L Mario, and JHU-MED). Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer. United States: N. p., 2010. Web. doi:10.1002/prot.22614.
Huang, Chuan-Hsiang, Gabelli, Sandra B, Oldfield, Eric, Amzel, L Mario, & JHU-MED). Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer. United States. https://doi.org/10.1002/prot.22614
Huang, Chuan-Hsiang, Gabelli, Sandra B, Oldfield, Eric, Amzel, L Mario, and JHU-MED). 2010. "Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer". United States. https://doi.org/10.1002/prot.22614.
@article{osti_1002858,
title = {Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer},
author = {Huang, Chuan-Hsiang and Gabelli, Sandra B and Oldfield, Eric and Amzel, L Mario and JHU-MED)},
abstractNote = {Bisphosphonates (BPs) are a class of compounds that have been used extensively in the treatment of osteoporosis and malignancy-related hypercalcemia. Some of these compounds act through inhibition of farnesyl diphosphate synthase (FPPS), a key enzyme in the synthesis of isoprenoids. Recently, nitrogen-containing bisphosphonates (N-BPs) used in bone resorption therapy have been shown to be active against Trypanosoma cruzi, the parasite that causes American trypanosomiasis (Chagas disease), suggesting that they may be used as anti-trypanosomal agents. The crystal structures of TcFPPS in complex with substrate (isopentenyl diphosphate, IPP) and five N-BP inhibitors show that the C-1 hydroxyl and the nitrogen-containing groups of the inhibitors alter the binding of IPP and the conformation of two TcFPPS residues, Tyr94 and Gln167. Isothermal titration calorimetry experiments suggest that binding of the first N-BPs to the homodimeric TcFPPS changes the binding properties of the second site. This mechanism of binding of N-BPs to TcFPPS is different to that reported for the binding of the same compounds to human FPPS.},
doi = {10.1002/prot.22614},
url = {https://www.osti.gov/biblio/1002858}, journal = {Proteins},
issn = {0887-3585},
number = (4) ; 03, 2010,
volume = 78,
place = {United States},
year = {Mon Nov 15 00:00:00 EST 2010},
month = {Mon Nov 15 00:00:00 EST 2010}
}