Sirtuins and Metabolic Pathway Integration

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DESCRIPTION (provided by applicant): Posttranslational modification is a rapid and efficient way in which cells adapt to changes in their environment. Biologists at large are interested in advancing our understanding of the mechanisms through which chemical modifications exert their effects, and want to learn more about the impact that these modifications have on the dynamics of the complex metabolic network of the cell. The long-term goal of the work supported by GM62203 is to understand the contributions of the sirtuin- dependent protein acylation/deacylation system (SDPADS) to prokaryotic cell physiology. Previous NIH funding of this project allowed us to advance our understanding of the role of the SDPADS in Gram- negative and Gram-positive bacteria. We are now in an excellent position to perform structure-function analyses of the acetyltransferase of the SDPADS, to dissect the regulation of expression of the genes encoding SDPADS functions, to identify the function of previously unknown genes also involved in acetylation control of protein activity, to establish a role for N-Lys protein acetylation/deacetylation in the control of central metabolic pathways, and to determine if prokaryotes use the SDPADS to directly control gene expression by modulating the activity of transcription regulators. We will take a multidisciplinary approach to answer fundamental questions of prokaryotic cell physiology. The first two aims of this proposal focus on newly discovered effects of acetylation on metabolism and gene expression, and the last two aims focus on the biochemical and structural characterization of the SDPADS enzymes and on the regulation of expression of the genes encoding SDPADS functions. Given the ubiquity of the SDPADS, advances in this research area will have broad impact on our understanding of the physiology of all cells. PUBLIC HEALTH RELEVANCE Rapid control of biological activities of proteins is critical for the survival of cells in a changing environment. Posttranslational modifications of lysine residues have a profound effect on gene expression and metabolism. The proposed work will advance our understanding of the mechanism of function of the modifying/demodifying enzymes that comprise a system conserved in all forms of life. Regulation of expression of the genes encoding the modifying/demodifying enzymes is part of the proposed studies. In this project we seek to validate putative new protein substrates of the system, including DNA-binding regulatory proteins.