Characterization of the biochemical and biological role of the MenA gene in asexual and sexual malarial stages

• Grant number: 15/12054-3
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): November 01, 2015
• Effective date (End): October 31, 2019
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Alejandro Miguel Katzin
• Grantee: Heloisa Berti Gabriel
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 17/00087-0 - Generation of a line that induces gametocyte production in P. knowlesi, BE.EP.PD

Abstract

Malaria is one of the main human parasites, consisting in a serious health problem worldwide, especially in African countries. Many efforts have been deployed in order to develop new treatments agents against the disease. The lack of an effective vaccine and the problem of drug resistance have challenged programs for malaria control and eradication. The search for new drug targets have focused in part on discovering metabolic pathways and the characterization of enzymes involved in these pathways as well as on screening and designing specific inhibitors that will combat the disease as well as control the transmission. Gametocytes (sexual stages) and asexual intraerythrocytic parasites have different developmental patterns that contribute to the differences in antimalarial sensitivity. In P. falciparum, we reported active menaquinone biosynthesis which is derived from the shikimate and MEP pathways. Our studies have shown inhibition of menaquinone biosynthesis by treatment with Ro 48-8071 (an inhibitor that targets the enzyme encoded by the MenA gene in Mycobacterium tuberculosis in the menaquinone biosynthesis). This project aims to: 1) Characterize an alternative menaquinone biosynthesis pathway in P. falciparum, 2) Characterize the enzymatic activity of the protein encoded by the MenA gene, a key enzyme of the menaquinone pathway and its biological role in asexual and gametocyte intraerythrocytic stages, 3) Test inhibitors of the menaquinone biosynthesis effective in asexual stages against gametocyte stages, 4) Use reverse genetics approach to determine the specificity of these inhibitors.

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)

GABRIEL, HELOISA B.; AZEVEDO, MAURO F.; KIMURA, EMILIA A.; KATZIN, ALEJANDRO M.. Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate. Memórias do Instituto Oswaldo Cruz, v. 113, n. 10, 2018. (17/22452-1, 14/23417-7, 15/12054-3, 15/19316-3, 16/15298-3)