Characterization of the protein phosphatase uis2 of Plasmodium as a new tool for malaria drug development

• Grant number: 12/50399-4
• Support Opportunities: Research Projects - SPEC Program
• Start date: October 01, 2012
• End date: September 30, 2015
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Victor Nussenzweig
• Grantee: Victor Nussenzweig
• Visiting researcher institution: New York University , United States
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Principal investigators: Min Zhang ; Ruth Nussenzweig

Abstract

We have previously shown that phosphrylation of eukaryotic initiation factor 2, more precisely a residue in the alpha subunit (elF2alpha), is a key regulatory process that arrests translation during the transition of Plasmodium parasites in the insect and during the intraerythrocytic stages. Preventing this phosphorylation by knocking down specific kinases prevents continuation of the parasite life cycle. In natural conditions elF2alpha is dephosphorylated and the relevant phosphatase has not yet been identified. Preliminary data suggest that a unique metallophosphatase (uis2) is required and we are performing experiments in sporozoites to confirm its direct involvement in eiF2alpha dephosphorylation. In this proposal, we plan to characterize this phosphatase, by expression in heterologous systems, and develop an assay that could be useful to identify new inhibitors, as potential hits for drug development against Malaria. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ZHANG, MIN; MISHRA, SATISH; SAKTHIVEL, RAMANAVELAN; FONTOURA, BEATRIZ M. A.; NUSSENZWEIG, VICTOR. UIS2: A Unique Phosphatase Required for the Development of Plasmodium Liver Stages. PLOS PATHOGENS, v. 12, n. 1, JAN 2016. (12/50399-4)

AUGUSTO, LEONARDO DA SILVA; MORETTI, NILMAR SILVIO; PRATA RAMOS, THIAGO CESAR; LEANDRO DE JESUS, TERESA CRISTINA; ZHANG, MIN; CASTILHO, BEATRIZ A.; SCHENKMAN, SERGIO. A Membrane-bound eIF2 Alpha Kinase Located in Endosomes Is Regulated by Heme and Controls Differentiation and ROS Levels in Trypanosoma cruzi. PLOS PATHOGENS, v. 11, n. 2, FEB 2015. (12/50399-4, 09/52047-5, 11/51973-3)