Regulation of intermediary metabolism by protein acetylation

Abstract

Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic analyses on protein acetylation uncovered a large number of acetylated proteins in the cytoplasm and mitochondria, including most enzymes involved in intermediate metabolism. Acetylation regulates metabolic enzymes by multiple mechanisms, including via enzymatic activation or inhibition, and by influencing protein stability. Conversely, non-nuclear NAD(+)-dependent sirtuin deacetylases can regulate cellular and organismal metabolism, possibly through direct deacetylation of metabolic enzymes. Furthermore, acetylation of metabolic enzymes is highly conserved from prokaryotes to eukaryotes. Given the frequent occurrence of metabolic dysregulation in diabetes, obesity and cancer, enzymes modulating acetylation could provide attractive targets for therapeutic intervention for these diseases.

Figure 1. Acetylation regulation of metabolic enzymes

Most intermediate metabolic enzymes are acetylated. The five major pathways that include enzymes whose regulation by acetylation has been characterized—gluconeogenesis (a), glycolysis (b), glycogen metabolism (C), fatty acid metabolism (d) and the urea cycle and nitrogen metabolism (e)--are illustrated. Substrates and products are colored in black. Metabolic enzymes are colored in red if their acetylations have been identified or blue if not. The red arrows, facing up or down, next to the enzymes indicate a stimulatory or inhibitory effect, respectively, on the enzyme activity by acetylation as determined by in vitro biochemical experiments