Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer.
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.
Huang
Chuan-Hsiang
CH
Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Gabelli
Sandra B
SB
Oldfield
Eric
E
Amzel
L Mario
LM
D000818:Animals; D002151:Calorimetry; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry* / Q000378:metabolism*; D051228:Geranyltranstransferase / Q000737:chemistry* / Q000378:metabolism*; D045782:Hemiterpenes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D014344:Trypanocidal Agents / Q000737:chemistry / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000201:enzymology*
D004164:Diphosphonates; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D014344:Trypanocidal Agents; C004809:isopentenyl pyrophosphate; D051228:Geranyltranstransferase; D009584:Nitrogen