The sugar glucose is essential to the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. Heretofore, we have known very little about the regulation of a key enzyme in glucose metabolism, hexokinase (TbHK1). Recently, our group has identified a second HK (TbHK2) that regulates the first. This observation, along with our finding that products from other cellular processes can alter HK activity, suggest that HK serves as a central mediator of metabolism in the cell. Here, we propose to explore how TbHK2 regulates TbHK1 at both the mRNA and protein levels. Further, we will consider how the enzyme is regulated by other mechanisms, including phosphorylation and inhibition by other cellular metbolites. Our long-term goal is to carefully characterize the roles of the two HKs in the biology of T. brucei, with a particular emphasis on understanding the role of these proteins in regulation of metabolism. We hypothesize that the proteins may regulate the cells'response to environmental changes in nutrient availability that occurs as the parasites move from one host to another.

Public Health Relevance

Trypanosoma brucei, the causative agent of African sleeping sickness, infects an estimated 500,000 people annually and is fatal if untreated. The research proposed here will further our understanding of the regulation of a metabolic pathway that is essential to the parasite suggesting that we may identify novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
3R15AI075326-01A1S1
Application #
7911534
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
2009-08-15
Project End
2011-08-31
Budget Start
2009-08-15
Budget End
2011-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$11,396
Indirect Cost
Name
Clemson University
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
042629816
City
Clemson
State
SC
Country
United States
Zip Code
29634
Flaherty, Daniel P; Harris, Michael T; Schroeder, Chad E et al. (2017) Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase?1. ChemMedChem 12:1994-2005
Hackler, Amber; Patrick, Stephen L; Kahney, Elizabeth W et al. (2017) Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids. Bioorg Med Chem Lett 27:755-758
Hackler, Amber L; Qiu, Yijian; Patrick, Stephen L et al. (2015) Characterization of an African trypanosome mutant refractory to lectin-induced death. Biochem Biophys Rep 4:33-38
Harris, M T; Mitchell, W G; Morris, J C (2014) Targeting protozoan parasite metabolism: glycolytic enzymes in the therapeutic crosshairs. Curr Med Chem 21:1668-78
Baker, Carol J; Carey, Vincent J; Rench, Marcia A et al. (2014) Maternal antibody at delivery protects neonates from early onset group B streptococcal disease. J Infect Dis 209:781-8
Harris, Michael T; Walker, Dawn M; Drew, Mark E et al. (2013) Interrogating a hexokinase-selected small-molecule library for inhibitors of Plasmodium falciparum hexokinase. Antimicrob Agents Chemother 57:3731-7
Lin, Sheng; Morris, Meredith T; Ackroyd, P Christine et al. (2013) Peptide-targeted delivery of a pH sensor for quantitative measurements of intraglycosomal pH in live Trypanosoma brucei. Biochemistry 52:3629-37
Joice, April C; Lyda, Todd L; Sayce, Andrew C et al. (2012) Extra-glycosomal localisation of Trypanosoma brucei hexokinase 2. Int J Parasitol 42:401-9
Stoner, Kevin A; Rabe, Lorna K; Austin, Michele N et al. (2011) Incidence and epidemiology of Streptococcus pseudoporcinus in the genital tract. J Clin Microbiol 49:883-6
Dodson, Heidi C; Morris, Meredith T; Morris, James C (2011) Glycerol 3-phosphate alters Trypanosoma brucei hexokinase activity in response to environmental change. J Biol Chem 286:33150-7

Showing the most recent 10 out of 40 publications