The parasite Plasmodium is the causative agent of the disease malaria. Among the species of Plasmodium that infects humans, Plasmodium falciparum is the deadliest, and it accounts for the majority of malaria infections worldwide. Unfortunately, the burden of these infections is particularly heavy in poor and undeveloped countries in Africa, South America and Asia. Currently, only a handful of metabolic processes have been verified as targets to treat malaria, and there is a growing need to identify agents that address other essential pathways. The seven-step shikimate pathway is essential to the production of aromatic amino acids, ubiquinone, and folate in bacteria and plants. While the shikimate pathway is also believed to be essential for apicomplexans, such as P. falciparum, the complete pathway cannot be identified in its genome. Recently, a bioinformatics study identified two predicted proteins in P. falciparum that are homologous to the last three enzymes in the shikimate pathway. Despite our inability to identify the rest of the pathway through bioinformatics analysis, there is compelling evidence that the P. falciparum shikimate pathway exists and is a viable drug target. Molecules known to target shikimate pathway enzymes in plants were found to inhibit P. falciparum growth. Additionally, the genes for the predicted shikimate pathway enzymes are transcriptionally active during all stages of the P. falciparum lifecycle. We propose to investigate the shikimate pathway in P. falciparum with the following specific aims: (1) Biochemically characterize the predicted P. falciparum shikimate pathway enzymes (shikimate kinase, 5-enolpyruvylshikimate-3-phosphate synthase, and chorismate synthase). (2) Identify other genes involved in shikimate biosynthesis in P. falciparum via a genetic complementation screen and metabolite analysis. (3) Determine if the shikimate pathway is essential to P. falciparum growth by identification of pathway specific inhibitors through small molecule screens, and the construction of genetic knockouts. We believe that these experiments are essential to determine if the shikimate pathway is a viable therapeutic target for the treatment of malaria.

Public Health Relevance

Malaria is a life-threatening disease that is caused by the Plasmodium parasite. I plan to investigate aromatic amino acid biosynthesis in Plasmodium falciparum, the deadliest species of the parasite, to evaluate the potential of the pathway as a drug target to treat malaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM093510-03
Application #
8225316
Study Section
Special Emphasis Panel (ZRG1-F04A-B (20))
Program Officer
Fabian, Miles
Project Start
2010-03-01
Project End
2012-08-31
Budget Start
2012-03-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$26,971
Indirect Cost
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Derbyshire, Emily R; Min, Jaeki; Guiguemde, W Armand et al. (2014) Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites. Antimicrob Agents Chemother 58:1516-22
Derbyshire, Emily R; Mazitschek, Ralph; Clardy, Jon (2012) Characterization of Plasmodium liver stage inhibition by halofuginone. ChemMedChem 7:844-9