The aim of this research is to use high field nuclear magnetic resonance spectroscopy to investigate the metabolic processes that occur in Trypanosoma cruzi and to use this information to help discover new drug targets. The methods to be employed for the further investigation of the metabolic processes in T cruzi involve the use of 600 and 750 MHz solution and solid-state NMR to study the 31P and 13C NMR spectroscopy of both epimastigote and amastigote forms. To date, initial 31P and 13C NMR spectra have been obtained, but the relationships between carbohydrate and phosphate metabolism, and amino acid and phosphate metabolism, have not been investigated. What needs to be done next, therefore, is to make the first correlations between carbon and phosphate metabolism, work that appears to be essential due to the very large levels of pyrophosphate found. That is, the role of pyrophosphate needs to be clarified. Here, the ability to monitor both soluble condensed phosphates (using solution NMR) as well as insoluble phosphates (using solid-state magic-angle sample-spinning techniques) should prove invaluable. Plus, solution and solid-state NMR techniques will be used to investigate the unusual poly-a-hydroxyoctanoate species found in T cruzi, which by analogy with the polyphosphate/poly-cx-hydroxybutyrate species found in prokaryotes may represent a primitive ion channel in the acidocalcisome.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM065782-02
Application #
6526891
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Whitmarsh, John
Project Start
2001-09-04
Project End
Budget Start
2002-09-04
Budget End
2003-09-03
Support Year
2
Fiscal Year
2002
Total Cost
$44,212
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Mao, Junhong; Mukherjee, Sujoy; Zhang, Yong et al. (2006) Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes. J Am Chem Soc 128:14485-97
Sanders, John M; Song, Yongcheng; Chan, Julian M W et al. (2005) Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption. J Med Chem 48:2957-63
Sanders, John M; Ghosh, Subhash; Chan, Julian M W et al. (2004) Quantitative structure-activity relationships for gammadelta T cell activation by bisphosphonates. J Med Chem 47:375-84
Garzoni, Luciana R; Caldera, Aura; Meirelles, Maria de Nazareth L et al. (2004) Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi. Int J Antimicrob Agents 23:273-85
Ghosh, Subhash; Chan, Julian M W; Lea, Christopher R et al. (2004) Effects of bisphosphonates on the growth of Entamoeba histolytica and Plasmodium species in vitro and in vivo. J Med Chem 47:175-87
Sanders, John M; Gomez, Aurora Ortiz; Mao, Junhong et al. (2003) 3-D QSAR investigations of the inhibition of Leishmania major farnesyl pyrophosphate synthase by bisphosphonates. J Med Chem 46:5171-83