|Assistant Professor (Research) in the Department of Biosciences||CG237||+44 (0) 191 33 43982|
Metabolism of Inositol Phosphates (IPs)
Phosphorous is an essential element virtually present in almost all reactions of cell metabolism. There are different phosphate-containing metabolites that enable cells to obtain, store and utilise this micronutrient. Inositol phosphates are a class of ubiquitous sugars containing phosphate substituents attached at different positions of the myo-inositol scaffold. The number and position of these Pi groups establishes a sort of inositide code that can be read by different proteins, thus playing regulatory or structural functions. How, where and why these metabolites are produced constitute one of the main focus of my research.
Trypanosomatid parasites as a model to study IPs biology
Trypanosomatids are a group of early-divergent eukaryotes with species that may cause diseases in animals or humans. They possess an intriguing cell organisation and metabolic features that are strikingly divergent from other ‘model’ organisms. The enzymology and regulation of their IPs-related kinase machinery make these organisms as an excellent model to explore IP biology. My current research focuses in understanding these atypical metabolic traits and exploit its potential to design rationale intervention strategies against these disease-causing parasites. We integrate gene editing techniques, high-resolution microscopy, proteomics, and phosphate chemistry methods to underpinning the biological functions of inositol phosphates with particular interest by inositol pyrophosphate (5-IP7).
Mantilla BS, Amaral LDD, Jessen HJ, Docampo R. The Inositol Pyrophosphate Biosynthetic Pathway of Trypanosoma cruzi. ACS Chem Biol. 2021 Jan 7.
Mantilla BS, Kalesh K, Brown NW Jr, Fiedler D, Docampo R. Affinity-based proteomics reveals novel targets of inositol pyrophosphate (5-IP7)-dependent phosphorylation and binding in Trypanosoma cruzi replicative stages. Mol Microbiol. 2020 Dec 22.
Marchese L, Olavarria K, Mantilla BS, Avila CC, Souza ROO, Damasceno FS, Elias MC, Silber AM. Trypanosoma cruzi synthesizes proline via a Δ1-pyrroline-5-carboxylate reductase whose activity is fine-tuned by NADPH cytosolic pools. Biochem J. 2020 May 29; 477(10):1827-1845.
Barisón MJ, Rapado LN, Merino EF, Furusho Pral EM, Mantilla BS, Marchese L, Nowicki C, Silber AM, Cassera MB. Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruzi epimastigotes. J Biol Chem. 2017 May 26; 292(21):8964-8977.
Mantilla BS, Marchese L, Casas-Sánchez A, Dyer NA, Ejeh N, Biran M, Bringaud F, Lehane MJ, Acosta-Serrano A, Silber AM. Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector. Plos Pathog. 2017 Jan 23;13(1):e1006158.
Mantilla BS, Paes LS, Pral EM, Martil DE, Thiemann OH, Fernández-Silva P, Bastos EL, Silber AM. Role of Δ1-pyrroline-5-carboxylate dehydrogenase supports mitochondrial metabolism and host-cell invasion of Trypanosoma cruzi. J Biol Chem. 2015 Mar 20;290(12):7767-90.
- Negrão, N. W., Crowe, L. P., Mantilla, B. S., Baptista, R. P., King-Keller, S., Huang, G., & Docampo, R. (2023). An X-Domain Phosphoinositide Phospholipase C (PI-PLC-like) of Trypanosoma brucei Has a Surface Localization and Is Essential for Proliferation. Pathogens, 12(3), Article 386. https://doi.org/10.3390/pathogens12030386
- Mantilla, B., Azevedo, C., Denny, P., Saiardi, A., & Docampo, R. (2021). The Histidine Ammonia Lyase of Trypanosoma cruzi is Involved in Acidocalcisome Alkalinization and is Essential for Survival under Starvation Conditions. mBio, 12(6), https://doi.org/10.1128/mbio.01981-21
- Barisón, M. J., Rapado, L. N., Merino, E. F., Furusho Pral, E. M., Mantilla, B. S., Marchese, L., …Cassera, M. B. (2017). Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruziepimastigotes. Journal of Biological Chemistry, 292(21), 8964-8977. https://doi.org/10.1074/jbc.m117.778522
- Mantilla, B. S., Marchese, L., Casas-Sánchez, A., Dyer, N. A., Ejeh, N., Biran, M., …Silber, A. M. (2017). Proline Metabolism is Essential for Trypanosoma brucei brucei Survival in the Tsetse Vector. PLoS Pathogens, 13(1), Article e1006158. https://doi.org/10.1371/journal.ppat.1006158
- Mantilla, B. S., Paes, L. S., Pral, E. M., Martil, D. E., Thiemann, O. H., Fernández-Silva, P., …Silber, A. 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. https://doi.org/10.1074/jbc.m114.574525
- Galvez Rojas, R. L., Ahn, I., Suárez Mantilla, B., Sant'Anna, C., Pral, E. M. F., & Silber, A. M. (2015). The Uptake of GABA inTrypanosoma cruzi. The Journal of Eukaryotic Microbiology, 62(5), https://doi.org/10.1111/jeu.12219
- Giordana, L., Mantilla, B. S., Santana, M., Silber, A. M., & Nowicki, C. (2014). Cystathionine γ-lyase, an Enzyme Related to the Reverse Transsulfuration Pathway, is Functional inLeishmaniaspp. The Journal of Eukaryotic Microbiology, 61(2), https://doi.org/10.1111/jeu.12100