We are interested in studying metabolism and drug development against protozoan parasites. We are particularly interested in understanding calcium signaling and storage in Toxoplasma gondii, an intracellular pathogen of humans and animals. It has been shown that calcium plays a critical role in T. gondii virulence but very little is known of the molecular mechanisms involved. Previous work from our laboratory characterized calcium rich acidic compartments in T. gondii and other protozoan parasites (Nature Rev. 3:251, 2005). Presently we are studying the role of extracellular calcium in parasite virulence and how acidic stores regulate calcium entry. We are specially interested in finding the molecular players involved which appear to be different from the mammalian cells ones. Our laboratory uses a variety of genetic tools and reagents available in our community to answer biochemical and physiological questions. Check the lab web site for more information.
We are presently studying the functions and biogenesis of this organelle. We are also interested in the isoprenoid pathway of Toxoplasma gondii (See scheme on the left). Work in collaboration with other laboratories is centered on testing isoprenoid pathway inhibitors against Toxoplasma growth in vitro and in vivo.
Isoprenoids are an extensive group of natural products with diverse structures consisting of various numbers of five carbon isopentenyl diphosphate (IPP) units. A central enzyme in the pathway, the farnesyl diphosphate synthase (FPPS) catalyzes the formation of farnesyl diphosphate (FPP), a precursor of critical molecules of fundamental biological functions such as dolichols, heme a, cholesterol, farnesylated proteins and others. This enzyme is a validated target for drugs and bisphosphonates, which are specific FPPS inhibitors, inhibit parasite growth in vitro and in vivo. Our hypothesis is that the isoprenoid pathway constitutes a major novel target for the treatment of toxoplasmosis.
Rohloff, P., Miranda, K., Rodrigues, J.C.F., Fang, J., Plattner, H., Hentschel, J., Galizzi, M. and Moreno, S.N.J. (2011) Calcium uptake and proton transport by acidocalcisomes of Toxoplasma gondii. Plos One. 2011 6(4):e18390.
Moreno, S.N.J., Ayong L. and Pace, D.A. Calcium storage and function in apicomplexan parasites. (2011). Invited chapter. Essays in Biochem. 51:97-110.
Nair, S., Brooks, C.F., Goodman, C.D., Strurm, A., McFadden, G.I., Sundriyal, S., Anglin, J.L., Song,Y., Moreno, S.N.J. and Striepen B. (2011) Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance. J. Exp. Med. 208:1547-1559
Francia, M.E. Wicher, S., Pace, D.A., Moreno, S.N.J., Arrizabalaga, G. (2011) A Toxoplasma protein with homology to intracellular type Sodium Hydrogen Exchangers is required for osmotolerance and protein processing. Exp. Cell Res. 317:1382
Pace, D.A., Fang, J., Cintron, R., Docampo, M.D., Moreno, S.N.J. (2011) Overexpression of a cytosolic pyrophosphatase (TgPPase) reveals a regulatory role of pyrophosphate on glycolysis in Toxoplasma gondii. Biochem. J. 440:229-240.
Miranda, K., Pace, D. A., Cintron-Moret, R., Rodrigues, J.C.F., Fang, J., Rohloff, P., Smith, A., Coelho, E., de Haas, F., J., de Souza, W., Coppens,I., Sibley, L.D. and Moreno, S.N.J. (2010). Characterization of a novel organelle in Toxoplasma gondii with similar composition and function to the plant vacuole. Mol. Microbiol. 76(6) 1358-1375.
Moreno, S.N.J., and Docampo, R. (2009) The role of acidocalcisomes in parasitic protists. J. Eukaryot. Microbiol. 56, 208-213.
Moreno S.N.J., Li Z.H. (2008). Targeting the isoprenoid pathway of Toxoplasma gondii. Expert Opin Ther Targets 12, 253-63.
Miranda, K. de Souza, W. Plattner, H. Hentschel, J. Kawazoe, U. and Moreno, SNJ. (2008) Acidocalcisomes in Apicomplexan parasites. Exp. Parasitol. 118, 2-9
Ling Y, Li ZH, Miranda K, Oldfield E, Moreno SN. The farnesyl diphosphate/geranylgeranyl diphosphate synthase of Toxoplasma gondii is a bifunctional enzyme and the molecular target of bisphosphonates (2007) J. Biol. Chem. 282, 30804-16.
Moreno, S.N.J., Miranda, K. and De Souza, W. (2007). Calcium homeostasis and acidocalcisomes in Toxoplasma gondii. In: The biology of Toxoplasma gondii. Eds: James Ajioka and Dominique Soldati. Horizon Scientific press. Chapter 26.
Moreno, S.N.J., Miranda, K., Fang, J., Rohloff, P. and de Souza. W. (2007) Calcium storage and homeostasis in Toxoplasma gondii. In: Toxoplasma gondii: The Model Apicomplexan---Perspective and Methods. Editors: Louis M. Weiss and Kami Kim. Elsevier-Academic Press. Chapter 10.
Harper JM, Huynh MH, Coppens I, Parussini F, Moreno S.N., Carruthers VB. A Cleavable Propeptide Influences Toxoplasma Infection by Facilitating the Trafficking and Secretion of the TgMIC2-M2AP Invasion Complex. (2006) Mol. Biol. Cell. 17(10):4551-63.
Ling, Y., Sahota, G., Odeh, S., Chan, J.M., Araujo, F., Moreno, S.N.J. and Oldfield, E. (2005) Bisphosphonate inhibitors of Toxoplasma gondii growth: in vitro, QSAR and in vivo investigations. J. Med. Chem. 48, 3130-3140.
Docampo, R., de Souza, W., Miranda, K., Rohloff, R., and Moreno, S.N.J. (2005) Acidocalcisomes –conserved from bacteria to man. Nat. Rev. Microbiol. 3, 251-261.
Arrizabalaga, G., Ruiz, F.A., Moreno, S.N.J., and Boothroyd, J.C. (2004) Ionophore-resistant mutant of Toxoplasma gondii reveals involvement of a sodium/hydrogen exchanger in calcium regulation. J. Cell Biol. 165, 653-662.