Dr Brian Suarez-Mantilla
Inositol phosphates are a class of soluble phosphate-rich metabolites that contain mono (IPs) or high-energy diphosphate (PP-IPs) groups (also known as pyrophosphates) attached to the six-carbon sugar myo-inositol. The number and positions of these phosphate-substituents is a key determinant in their biological role, thus establishing a sort of phosphate-code with at least 64 isomeric forms1. IPs and PP-IPs are enzymatically produced by a family of kinases that transfer a phosphate group from ATP into a phosphorylated specie of myo-inositol. Trypanosomes are early-divergent eukaryote parasites with a unique and well-defined cell architecture. They are responsible for multiple diseases affecting humans and animals. These parasites possess all the enzymatic machinery to meet their demand of PPs/PP-IPs2, and proteins that bind to IPs/PP-IPs have also been described. For instance, their I(1,4,5)P3 receptor (IP3R) is localized at the membrane of acidocalcisomes mediating the release of Ca2+ from these stores to the cytosol3. SPX domain-containing proteins involved in phosphate homeostasis4 are also conserved in these species and, recently, a protein screen using 5-diphosphoinositol pentakisphosphate (5PP-IP5, also known as inositol pyrophosphate or IP7) as bait enabled the identification of components participating in multiple cellular processes suggesting a role for 5PP-IP5 in essential pathways of this parasite. Vesicular trafficking, purine nucleotides, phosphate homeostasis and, lipids catabolism are amongst the most intriguing routes in the biology of these parasites which highlights the importance of these phosphate-metabolites. Our research will be focused in defining and characterizing the essential processes controlled by inositol pyrophosphates in Leishmania and T. cruzi parasites. The genetic tractability gained for these organisms after emerging of genome-editing approaches enables better opportunities for functional characterization of distinct cellular targets. By deploying CRISPR/Cas9-based methods, metabolic profiling, enzymatic studies, high-resolution microscopy and proximity-dependent labelling methods for proteomic analysis, it will be dissected how these parasites use inositol diphosphates to ensure their persistence within their mammalian-host. The evidences obtained through these studies will pave the way of novel alternatives for therapeutics.
 Irvine, R. F., and Schell, M. J. (2001) Back in the water: the return of the inositol phosphates, Nat Rev Mol Cell Biol 2, 327-338.
 Cordeiro, C. D., Saiardi, A., and Docampo, R. (2017) The inositol pyrophosphate synthesis pathway in Trypanosoma brucei is linked to polyphosphate synthesis in acidocalcisomes, Mol Microbiol 106, 319-333.
 Huang, G., Bartlett, P. J., Thomas, A. P., Moreno, S. N., and Docampo, R. (2013) Acidocalcisomes of Trypanosoma brucei have an inositol 1,4,5-trisphosphate receptor that is required for growth and infectivity, Proc Natl Acad Sci U S A 110, 1887-1892.
 Potapenko, E., Cordeiro, C. D., Huang, G., Storey, M., Wittwer, C., Dutta, A. K., Jessen, H. J., Starai, V. J., and Docampo, R. (2018) 5-Diphosphoinositol pentakisphosphate (5-IP7) regulates phosphate release from acidocalcisomes and yeast vacuoles, J Biol Chem 293, 19101-19112.
Department of Biosciences
- Barisón, María Julia, Rapado, Ludmila Nakamura, Merino, Emilio F., Furusho Pral, Elizabeth Mieko, Mantilla, Brian Suarez, Marchese, Letícia, Nowicki, Cristina, Silber, Ariel Mariano & Cassera, Maria Belen (2017). Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruziepimastigotes. Journal of Biological Chemistry 292(21): 8964-8977.
- Mantilla, Brian S., Marchese, Letícia, Casas-Sánchez, Aitor, Dyer, Naomi A., Ejeh, Nicholas, Biran, Marc, Bringaud, Frédéric, Lehane, Michael J., Acosta-Serrano, Alvaro & Silber, Ariel M. (2017). Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector. PLOS Pathogens 13(1): e1006158.
- Mantilla, Brian S., Paes, Lisvane S., Pral, Elizabeth M. F., Martil, Daiana E., Thiemann, Otavio H., Fernández-Silva, Patricio, Bastos, Erick L. & Silber, Ariel M. (2015). Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion ofTrypanosoma cruzi. Journal of Biological Chemistry 290(12): 7767-7790.
- Galvez Rojas, Robert L., Ahn, Il-Young, Suárez Mantilla, Brian, Sant'Anna, Celso, Pral, Elizabeth Mieko Furusho & Silber, Ariel Mariano (2015). The Uptake of GABA inTrypanosoma cruzi. Journal of Eukaryotic Microbiology 62(5): 629.
- Giordana, Lucila, Mantilla, Brian Suárez, Santana, Marianela, Silber, Ariel M. & Nowicki, Cristina (2014). Cystathionine γ-lyase, an Enzyme Related to the Reverse Transsulfuration Pathway, is Functional inLeishmaniaspp. Journal of Eukaryotic Microbiology 61(2): 204.