Chemistry of Mitochondrial Protein Acetylation:Evolution of Substrate Reactivity as a Regulatory Mechanism

University Of Iowa, Iowa City IA

Investigators

Abstract

All cellular life depends on enzymatic activities that break down fuels and transforms small molecules into big ones. Enzyme functions are tuned by modifications, which are typically added by other specialized enzymes. In mitochondria, the energy powerhouses of cells, many enzymes are inhibited by addition of a 2-carbon unit termed acetyl, which is also a common currency in mitochondrial fuel oxidation. These changes have important consequences for the balance between energy generation and fat storage. The applicants proposed that acetyl modification of mitochondrial enzymes is driven by chemical reactivity rather than enzyme activity. They aim to lead an interdisciplinary and international research team to test this hypothesis and to predict chemical reactivity from enzyme structures. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Drs. Charles Brenner and Michael Schnieders to determine whether they can explain the rates of protein acetylation of mitochondrial enzymes from first chemical principles, namely depression of lysine pKa values by nearby positive charges and partial desolvation. They will combine experimental techniques and novel computational methods to determine rates of chemical acetylation and to predict sidechain pKa values. Because mitochondrial enzymes are frequently inactivated by protein acetylation and this has been proposed to drive fuel-sensitive metabolic changes, the project may also be able to explain how animals evolved chemical mechanisms to maximize weight gain during times of over-nutrition and to minimize weight loss during calorie restriction.