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

Proteins. 2010 Mar;78(4):888-99. doi: 10.1002/prot.22614.

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. Proteins 2010. (c) 2009 Wiley-Liss, Inc.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calorimetry
  • Crystallography, X-Ray
  • Diphosphonates / chemistry*
  • Diphosphonates / metabolism*
  • Geranyltranstransferase / chemistry*
  • Geranyltranstransferase / metabolism*
  • Hemiterpenes / chemistry
  • Hemiterpenes / metabolism
  • Humans
  • Molecular Structure
  • Nitrogen / chemistry*
  • Organophosphorus Compounds / chemistry
  • Organophosphorus Compounds / metabolism
  • Protein Structure, Secondary
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / metabolism
  • Trypanosoma cruzi / enzymology*

Substances

  • Diphosphonates
  • Hemiterpenes
  • Organophosphorus Compounds
  • Trypanocidal Agents
  • isopentenyl pyrophosphate
  • Geranyltranstransferase
  • Nitrogen