This program is devoted to studying structure-function of proteins from a number of pathogenic parasites.  Parasitic diseases pose major public health threat worldwide.  Research in our laboratory seeks to improve our understanding of the biochemical and biological processes regulating the life cycle of these parasites with the ultimate goal of identifying exploitable drug targets for developing chemotherapeutic strategy.  Currently there are three proteins under this program.

Folate metabolic pathway of Trypanosoma cruzi

Trypanosoma cruzi is a protozoan parasite which causes Chagas’ disease.  The disease affects 16-18 million people and causes 50,000 deaths annually.  Despite the enormous global burden of Chagas’ disease, no drug is effective in chronic stage and those used for treatment of acute disease result in toxic side effects.  With more than 100 million people in 20 countries at risk, yet no hope for a vaccine in the foreseeable future, there is an urgent need for effective chemotherapy for millions of infected individuals.  Drugs targeting folate metabolic enzymes have been remarkably successful in the treatment of infectious diseases including parasitic diseases such as malaria.  Our research currently focuses on the application of a three dimensional structure-based approach for designing specific and potent inhibitors of T. cruzi dihydrofolate-thymidylate synthase enzyme.  Crystal structures of the bifunctional enzyme in complex with substrates and inhibitor have been determined.  We have identified a low nanomolar inhibitor of the enzyme as a potent inhibitor of the T. cruzi parasite.

The following proteins of T. cruzi have been studied in our laboratory:

	Pteridine reductase 1 (PTR1): Pterin metabolism and antifolate resistance.
	Crystallized.
	Pteridine reductase 2 (PTR2): Pterin metabolism and antifolate resistance.
	Structure determined at 2.2Å resolution.  PDBID: 1MXH and 1MXF.
	Dihydrofolate reductase (DHFR): Involved in folate metabolism.
	Crystallized.
	Dihydrofolate reductase-thymidylate synthase (DHFR-TS): Involved in folate metabolism and DNA synthesis.
	Crystallized.

Protein trafficking machinery of Plasmodium falciparum

Soon after infecting the human host the malaria parasite enters the red blood cells where it multiplies and actively modifies the host cells.  Most of the pathophysiological conditions of human malaria caused by P. falciparum are associated with this intraerythrocytic stage.  Inside the erythrocyte the parasites are surrounded by three layers of membrane: the parasitophorous vacuole membrane (PVM), the parasites own plasma membrane and the red blood cells own membrane.  Yet the parasite encoded proteins are able to transport from inside the parasite all the way to the outer surface of red blood cells.  Proteins displayed on the surface of red blood cells are strategically important for the survival of the parasite and of great significance to the disease outcome.  Understanding the mechanism of protein trafficking by P. falciparum is therefore of great interest.  Our laboratory focuses on the vesicle mediated trafficking machinery of P. falciparum.

The following proteins of P. falciparum have been studied in our laboratory:

	Rab6 GTPase: Involved in intracellular trafficking.
	Structure determined at 2.5Å resolution.   PDBID: 1D5C.
	ADP-ribosylation factor 1 (ARF-1): Involved in intracellular trafficking.
	Structure determined at 2.4Å resolution.
	ARF-GTPase Activating Protein (ARF-GAP): Involved in intracellular trafficking.
	Structure determined at 2.9Å resolution.
	3-Phosphoglycerate kinase (3-PGK): ATP generating enzyme in glycolytic pathway.
	Structure determined at 3.0Å resolution.   PDBID: 1LTK.
	Lactate dehydrogenase (LDH): Terminal enzyme in glycolytic pathway.
	Structure in complex with pyruvate & NAD, and pyruvate & APAD determined at 1.7Å resolution.
	Rab11GTPase: Involved in intracellular trafficking.
	Expressed.
	Glyceraldehyde 3-phosphate dehydrogenase: Glycolytic enzyme
	Expressed.
	Cytoplasmic Malate dehydrogenase.
	Crystallized.

Other parasitic enzymes studied in our laboratory:

	Cryptosporidium parvum - Lactate dehydrogenase (LDH): Key glycolytic enzyme.
	Structure determined at 2.9Å resolution.
	Cryptosporidium parvum - Pyruvate kinase (PyK): Rate limiting glycolytic enzyme.
	Crystallized.
	Cryptosporidium parvum - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH): Key glycolytic enzyme.
	Crystallized.
	Toxoplasma gondii - Adenosine kinase (AK):
	Structure determined at 1.8Å resolution.  PDBID: 1DGM.
	Toxoplasma gondii - Uracil phosphoribosyltransferase (UPRT):
	Toxoplasma gondii - Uracil phosphoribosyltransferase (UPRT):
	Leishmania donovani - Adenosine kinase (AK):
	Crystallized.