Comparative Mechanistic and Structural Analysis of Apicomplexan Phosphoethanolamine N-Methyltransferases for Broad-Spectrum Antiparasitic Discovery

About This Grant

PROJECT SUMMARY Protozoan parasites, together with helminths, account for approximately 25% of all human infections worldwide, with humans hosting more than 70 species of protozoa. Within this group, apicomplexan parasites cause severe diseases including malaria, opportunistic infections, and foodborne outbreaks that impose significant health risks and socioeconomic burdens in both resource-limited settings and developed nations, including the United States. In this project, we will investigate apicomplexan phosphoethanolamine N-methyltransferases (PMTs), essential enzymes required for phosphatidylcholine biosynthesis but absent from mammalian genomes. We will comparatively characterize the molecular mechanisms of apicomplexan PMTs from multiple human and animal apicomplexan parasites including Plasmodium, Cyclospora, Toxoplasma, and Eimeria. This project will integrate comparative genomics, enzymology, biophysics, and mutagenesis to elucidate the mechanistic features of apicomplexan PMTs, including catalytic mechanisms, kinetic parameters, and ligand- recognition determinants (Aim 1). We will also utilize artificial intelligence and machine learning (AI/ML)- supported structural analysis with complementary computational and experimental validation to determine high- resolution structures and map conserved versus variable ligand-binding regions (Aim 2). The resulting structure- function relationships will identify potentially druggable binding pockets for selective small-molecule inhibitor development and provide foundational knowledge to enable both broad-spectrum and lineage-specific antiparasitic therapeutics. Furthermore, this proposed research integrates well-established methodologies with advanced instrumentation accessible to graduate and undergraduate researchers, including students in the Course-based Undergraduate Research Experience (CURE), thereby advancing biomedical research while strengthening innovative STEM education at Kennesaw State University (KSU).