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Biochemical characterization of an Atypical Polyketide Synthase (PKS) from the apicomplexan Pasarite Toxoplama gondii

Ph.D. Defense- Keeler, Aaron
Tuesday, November 21, 2023
9:30 am - 10:30 am
Aaron Keeler, Ph.D. Candidate

Aaron Keeler, Ph.D. Candidate

Emily Derbyshire Ph.D., Advisor

Abstract: The phylum Apicomplexa encompasses multiple obligate intracellular parasites that pose significant human health burdens including the causative agents of malaria, toxoplasmosis, and cryptosporidiosis which infect millions and cause thousands of deaths each year. During their complex life cycles, apicomplexan parasites coordinate the function of specific proteins to evade the host immune system and thrive under stressful conditions. Currently, these protists are underexplored for biosynthetic potential, however research points to this kingdom as an untapped source for new chemical space. In this defense, I will present work toward understanding polyketide synthase (PKS) genes within Toxoplasma gondii through 1) sequence elucidation and initial domain characterization of a novel T. gondii PKS, TgPKS2, 2) uncovering an unprecedented self-acylation activity within specific carrier proteins in this synthase, and 3) exploring the unusual chain release mechanism present in this system. First, I will investigate the architecture and show our initial studies on TgPKS2 including hydrolysis activities of acyltransferase (AT) domains, mutagenesis studies, and a first of its kind self-acylation activity of acyl carrier protein (ACP) domains in a modular type I PKS. Next, I will emphasize the unique attributes of TgPKS2 by comparing its transacylation activity to well-characterized bacterial and fungal systems. Lastly, I will share our exploration into a never before characterized chain release mechanism present in this synthase, and explore the likely importance of this synthase in parasite biology. Combined, this work encompasses our efforts to characterize TgPKS2, discover the role it plays within the T. gondii life cycle, and elucidate the metabolite(s) produced.