The proposed research seeks to study the functions and regulation of bacterial polyamine acetyltransferases (PAATs). These enzymes belong to the large Gcn5-related N-acetyltransferase (GNAT) superfamily, and acetylate a variety of polyamines including spermine, spermidine, and norspermidine. The main function associated with bacterial PAATs has been to maintain intracellular polyamine concentrations; however, increasing evidence has shown that PAATs likely play a larger role in bacterial physiology and pathogenesis than previously anticipated. While PAATs have been well-studied in eukaryotes, there is a significant gap in knowledge regarding bacterial PAAT identities, functions and regulation. Additionally, there is a limited understanding of how allosteric effectors and oligomerization regulate PAAT function, and how these properties effect PAAT roles in bacterial biofilms and other cellular processes. Since polyamines have been implicated in bacterial virulence and pathogenesis, knowledge about PAAT regulation is critical for developing effective therapeutics toward bacterial pathogens. Therefore, the goal of the proposed research is to determine the roles of PAATs and how they are regulated across pathogenic and non-pathogenic bacteria. We will investigate the following key questions over the next five years: 1) Which bacterial GNATs are PAATs?, 2) How are bacterial PAATs regulated?, and 3) How do bacterial PAATs regulate cellular processes?. The answers to these questions will yield insight into PAAT evolution and distribution across bacteria, identify strategies for targeted therapeutics, and add to the fundamental knowledge of PAAT function and regulatory properties in bacteria.
The research projects presented in this proposed work will lay the foundation for understanding fundamental processes and regulation of bacterial polyamine acetyltransferases, which belong to the important Gcn5- related N-acetyltransferase superfamily. These enzymes affect a variety of biological process and are known to be critical for survival and persistence of bacterial pathogens. Our work will provide new insight for developing potential therapeutics in the future.