Evaluation of Plasmodium falciparum 4-hydroxybenzoate polypreniltranferase (PfUbiA) in ubiquinone biosynthesis

• Grant number: 19/04579-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2019
• End date: December 31, 2021
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Alejandro Miguel Katzin
• Grantee: Camila Andrea Zafra Alba
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Previously our group identified in the intraerythrocytic stages of Plasmodium falciparum the biosynthesis of several isoprenylated molecules including prenylquinones with respiratory function in most organisms such as menaquinone-4 (MQ-4) and isoforms of ubiquinone-7, 8 and 9 (UQ). However, the biological role of both MQ-4 and the three different isoforms of UQ is not well understood. Previously the student had an internship in the group and collaborated actively in the study of the biosynthesis of UQ. In this period the biosynthesis of UQ under different environmental conditions and the effects of the antimalarial atovaquone (inhibitor of the mitochondrial complex III) were studied. The results indicate that increased oxygen saturation appears to trigger an increase in the intracellular pool of UQs and this may be the cause of the reduction of the effect of atovaquone under these conditions. The absence of oxygen or even atovaquone only modifies the UQ-9 indicating as the most involved in mitochondrial activity. The effect of atovaquone on parasite viability can be reversed by decil-UQ (UQ analogue), but not by MQ-4 demonstrating the essentiality of UQ among other prenylquinones in respiration. Already, the pharmacological inhibition of the enzyme 4-hydroxybenzoate polyprenyltranferase of P. falciparum (PfUbiA), the first enzyme in the biosynthesis pathway of UQ by 4-nitrobenzoate has been shown to improve the efficacy of atovaquone. In this project we propose to evaluate the PfUbiA in the biosynthesis of UQ. Essentially we propose to study the functionality of the enzyme by complementation in yeast and define which is the aromatic donor. The study opens up opportunities for the rational development of new pharmacological combinations and should deepen the knowledge of the bioenergetic metabolism of the parasite. (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)

ZAFRA, CAMILA ANDREA; CRISPIM, MARCELL; VERDAGUER, IGNASI BOFILL; RIOS, ALEJANDRO GARCIA; MOURA, GABRIEL CANDIDO; KATZIN, ALEJANDRO MIGUEL; HERNANDEZ, AGUSTIN. Plasmodium falciparum COQ2 gene encodes a functional 4-hydroxybenzoate polyprenyltransferase. FEMS Microbiology Letters, v. 370, p. 8-pg., 2023-01-17. (19/04579-0, 17/22452-1)