Analyzing structure, function and dynamics of vitamin B6 biosynthesis enzymes from Plasmodium vivax

• Grant number: 19/26428-3
• Support type: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): February 05, 2021
• Effective date (End): October 31, 2021
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal researcher: Alessandro Silva Nascimento
• Grantee: Angélica Luana Carrillo Barra
• Supervisor abroad: Christian Jochen Betzel
• Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Research place: Universität Hamburg (UHH), Germany
• Associated to the scholarship: 18/21213-6 - Structural characterization of vitamin B1 and B6 synthesis pathway enzymes in Plasmodium falciparum and Mycobacterium tuberculosis, BP.DD

Abstract

Infectious diseases are one of the leading causes of death in the world, and the number of antimicrobial-resistant infectious is continuously increasing. Plasmodium sp. is among the main multidrug-resistant pathogens making malaria treatment difficult. According to the World Health Organization, malaria is responsible for 435 thousand deaths per year worldwide and 40% of the cases are due to Plasmodium vivax. These data highlight the urgency to identify novel therapeutic targets for antimicrobial development. The advancement of complete genome sequencing allows the identification of enzymes and pathways that are preserved in many pathogens but absent in humans and, thus, are desirable targets for antimicrobial drug discovery. An example of a pathogen-specific pathway is the vitamin B6 (pyridoxal phosphate) de novo synthesis pathway. Pyridoxal 5-phosphate (PLP) is an essential cofactor for various enzymes in all organisms which are involved in the biosynthesis of amino compounds such as amino acids. A complex of two enzymes, Pdx1 and Pdx2, performs the synthesis of PLP. Pdx2 has a glutaminase activity and delivers an ammonia molecule to Pdx1, which synthesizes PLP using ammonia, ribose 5-phosphate and glyceraldehyde 3-phosphate. Based on that, this project proposes the structural investigation of the plasmodial PLP synthase complex as a possible target for prodrugs discovery against P. vivax. (AU)