Malaria, a disease caused by protozoan parasites, is one of the most dangerous infectious diseases, claiming millions of lives and infecting hundreds of millions of people annually. Malaria parasites contain an essential organelle called the apicoplast that is thought to have arisen through endosymbiosis of an algal cell which had previously incorporated a cyanobacterium. Due to its prokaryotic origin, the apicoplast contains a range of metabolic pathways that differ significantly from those of the human host. We are investigating biochemical pathways found in the apicoplast, particularly those required for the biosynthesis and modification of fatty acids. This metabolism should require several enzyme cofactors such as pantothenate, lipoic acid, biotin and iron-sulfur clusters. We are interested in these cofactors, how they are acquired, how they are used, and whether they are essential for the growth of blood stage malaria parasites. We approach these questions with a combination of cell biology, genetic, biophysical and biochemical techniques.

Molecular Microbiology and Immunology, malaria, fatty acid biosynthesis, apicoplast, x-ray crystallography, enzymology

Gallagher JR and Prigge ST. Plasmodium falciparum acyl carrier protein crystal structures in disulfide-linked and reduced states and their prevalence during blood stage growth. Proteins, in press.

Ben Mamoun C, Prigge ST, Vial H. Targeting the Lipid Metabolic Pathways for the treatment of Malaria. Drug. Dev. Res. in press.

Spalding MD and Prigge ST. The Aminohydrolase Domain of Lipoamidase Functions as an Inducible Probe of Protein Lipoylation in vivo. PLOS One, 4, e7392 (2009).

Lee PJ, Bhonsle JB, Gaona HW, Huddler DP, Heady TN, Kreishman-Deitrick M, Bhattacharjee A, McCalmont WF, Gerena L, Lopez-Sanchez M, Roncal NE, Hudson TH, Johnson JD, Prigge ST, Waters NC, Targeting the Fatty Acid Biosynthesis enzyme, PfKASIII, in the identification of novel antimalarial agents. J. Med. Chem. 52, 952-963 (2009).

Spalding MD and Prigge ST, Malaria pulls a FASt one. Cell Host & Microbe, 4, 509-511 (2008).

Lu JZ and Prigge ST, The tail of mycolic acids. Chem. Biol. 4, 309-310 (2008).

Allary M and Prigge ST, Fatty Acid Synthesis in Protozoan Parasites. In: Encyclopedia of Life Sciences (ELS), John Wiley & Sons, Ltd: Chichester (2008).

Lu JZ, Muench SP, Allary M, Campbell SA, Roberts CW, Mui E, McLeod RL, Rice DW, Prigge ST. Type I and Type II Fatty Acid Biosynthesis in Eimeria tenella: Enoyl Reductase Activity and Structure. Parasitology 134, 1949-1962 (2007).

Allary M, Lu JZ, Zhu L, Prigge ST. Scavenging of the cofactor lipoate is essential for the survival of the malaria parasite Plasmodium falciparum. Mol. Micro. 63, 1331-44 (2007).

Muench SP, Prigge ST, McLeod R, Rafferty JB, Kirisits MJ, Roberts CW, Mui EJ, Rice DW. Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents. Acta Crystallogr D Biol Crystallogr. 63, 328-38 (2007).

Ferguson DJ, Campbell SA, Henriquez FL, Phan L, Mui E, Richards TA, Muench SP, Allary M, Lu JZ, Prigge ST, Tomley F, Shirley MW, Rice DW, McLeod R, Roberts CW. Enzymes of type II fatty acid synthesis and apicoplast differentiation and division in Eimeria tenella. Int J Parasitol. 37, 33-51 (2007).

Muench SP, Prigge ST, Zhu L, Kirisits MJ, Roberts CW, Wernimont S, McLeod R, Rice DW. Expression, purification and preliminary crystallographic analysis of the Toxoplasma gondii enoyl reductase. Acta Crystallograph Sect F Struct Biol Cryst Commun. 62, 604-6 (2006).

Chen Y, Jirage D, Caridha D, Kathcart AK, Cortes EA, Dennull RA, Geyer JA, Prigge ST, Waters NC. Identification of an effector protein and gain-of-function mutants that activate Pfmrk, a malarial cyclin-dependent protein kinase. Mol Biochem Parasitol. 149, 48-57 (2006).

Geyer JA, Prigge ST, Waters NC. Targeting malaria with specific CDK inhibitors. Biochim Biophys Acta. 1754, 160-70 (2005).

Siebert X, Eipper BA, Mains RE, Prigge ST, Blackburn NJ, Amzel LM. The catalytic CuB site of PHM also plays a critical structural role. Biophys. J. 89, 3312-3319 (2005).

Geyer JA, Prigge ST, Waters NC. Targeting malaria with specific CDK inhibitors. Biochim. Biophys. Acta. (2005).

Ferguson DJP, Samuel BU, Henriquez FL, Kirisits MJ, Muench SP, Prigge ST, Rice DW, Roberts CW, McLeod RL, Stage specific variation in the apicoplast and associated enoyl reductase in Toxoplasma gondii during development in the intermediate and definitive host. Eukaryotic. Cell 4, 814-826 (2005).

Lu JZ, Lee PJ, Waters NC, Prigge ST. Fatty Acid synthesis as a target for antimalarial drug discovery. Comb Chem High Throughput Screen 8, 15-26 (2005).

Keenan SM, Geyer JA, Welsh WJ, Prigge ST, Waters NC. Rational inhibitor design and iterative screening in the identification of selective plasmodial cyclin dependent kinase inhibitors. Comb Chem High Throughput Screen 8, 27-38 (2005).

Prigge ST, Eipper BA, Mains RE, Amzel LM. Dioxygen binds end-on to mononuclear copper in a precatalytic enzyme complex. Science 304, 864-7 (2004).

Bhattacharjee AK, Geyer JA, Woodard CL, Kathcart AK, Nichols DA, Prigge ST, Li Z, Mott BT, Waters NC. A three-dimensional in silico pharmacophore model for inhibition of Plasmodium falciparum cyclin-dependent kinases and discovery of different classes of novel Pfmrk specific inhibitors. J Med Chem 47, 5418-26 (2004).

Bujnicki JM, Prigge ST, Caridha D, Chiang PK. Structure, evolution, and inhibitor interaction of S-adenosyl-L-homocysteine hydrolase from Plasmodium falciparum. Proteins 52, 624-32 (2003).

Woodard CL, Li Z, Kathcart AK, Terrell J, Gerena L, Lopez-Sanchez M, Kyle DE, Bhattacharjee AK, Nichols DA, Ellis W, Prigge ST, Geyer JA, Waters NC. Oxindole-based compounds are selective inhibitors of Plasmodium falciparum cyclin dependent protein kinases. J Med Chem 46, 3877-82 (2003).

Samuel BU, Hearn B, Mack D, Wender P, Rothbard J, Kirisits MJ, Mui E, Wernimont S, Roberts CW, Muench SP, Rice DW, Prigge ST, Law AB, McLeod R. Delivery of antimicrobials into parasites. Proc Natl Acad Sci U S A 100, 14281-6 (2003).

Prigge ST, He X, Gerena L, Waters NC, Reynolds KA. The initiating steps of a type II fatty acid synthase in Plasmodium falciparum are catalyzed by pfACP, pfMCAT, and pfKASIII. Biochemistry 42, 1160-9 (2003).

Muench SP, Rafferty JB, McLeod R, Rice DW, Prigge ST. Expression, purification and crystallization of the Plasmodium falciparum enoyl reductase. Acta Crystallogr D Biol Crystallogr 59, 1246-8 (2003).

Waters NC, Kopydlowski KM, Guszczynski T, Wei L, Sellers P, Ferlan JT, Lee PJ, Li Z, Woodard CL, Shallom S, Gardner MJ, Prigge ST. Functional characterization of the acyl carrier protein (PfACP) and beta-ketoacyl ACP synthase III (PfKASIII) from Plasmodium falciparum. Mol Biochem Parasitol 123, 85-94 (2002).