Sirtuins and Metabolic Pathway Integration

University Of Wisconsin-Madison, Madison WI

Investigators

Linked publications & trials

Abstract

Cells respond to physiological stresses brought about by a changing environment in different ways. The control of the biological function of proteins, nucleic acids, and small molecules by chemical modifications is a rapid and efficient way in which cells adapt to change. 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 our work is to understand the contributions of the sirtuin-dependent protein acylation/deacylation system (SDPADS) to prokaryotic cell physiology. Although we discovered the SDPADS during the analysis of short-chain fatty acid catabolism, knowledge gained during the last funding period of GM62203 revealed new insights into the breadth of this modification system in regulating cell function. We advanced our understanding of several areas of cell physiology, including posttranslational control of protein function by acylation;CoA homeostasis and its relevance to microbial pathogenesis;metabolic pathway integration;and elucidation of gene function. Notably, we obtained the first in vivo and in vitro evidence of SDPADS-dependent protein control by propionylation in any organism. We also extended our analysis of protein acylation/deacylation to Gram-positive bacteria using Bacillus subtilis as a model organism. We are now in an excellent position to begin investigating the regulation of expression of the genes encoding SDPADS functions, to identify the function of previously unknown genes and characterize the role of N-Lys protein acetylation/deacetylation in the pentose phosphate pathway, and to determine if prokaryotes use the SDPADS to directly control gene expression by modulating the activity of transcription regulators. The first aim of this proposal focus on newly discovered effects of acetylation on gene expression, and the second aim focuses on the regulation of expression of the cobB gene, which encodes the NAD+- dependent protein deacetylase in S. enterica. Given the ubiquity of the SDPADS, advances in this research area will have broad impact on our understanding of the physiology of all cells. Comprehensive genetic, molecular biological, and biochemical approaches will be taken to answer fundamental questions of prokaryotic cell physiology.