Mechanistic insights into the regulation of metabolic enzymes by acetylation

Abstract

The activity of metabolic enzymes is controlled by three principle levels: the amount of enzyme, the catalytic activity, and the accessibility of substrates. Reversible lysine acetylation is emerging as a major regulatory mechanism in metabolism that is involved in all three levels of controlling metabolic enzymes and is altered frequently in human diseases. Acetylation rivals other common posttranslational modifications in cell regulation not only in the number of substrates it modifies, but also the variety of regulatory mechanisms it facilitates.

Figure 1.

Acetylation regulates the amount of metabolic enzymes. Acetylation can regulate the steady-state levels of metabolic enzymes by promoting their degradation through either the ubiquitin–proteasomal system in the case of phosphoenolpyruvate carboxykinase (PCK1; A) or CMA in the case of PK M2 isoform (PKM2; B). Metabolic enzymes and acetylated lysine residues (K) are colored in light green and purple, respectively. Active sites are indicated by three red radial dashes.

Figure 2.

Acetylation regulates the catalytic activity of metabolic enzymes. Acetylation can regulate the catalytic activity of metabolic enzymes through directly neutralizing the positive charge of lysine residues in the active site of OTC (A), recruiting a negative regulator such as phosphatase (PPase) to inhibit GP (B), or causing allosteric changes in 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2; C). Enzymes, acetylated lysine residues (K), and active sites are labeled as in Fig. 1. S, substrate.

Figure 3.

Acetylation regulates the substrate accessibility to metabolic enzymes. (A) Acetylation can regulate the substrate accessibility to metabolic enzymes by modifying the conserved lysine residues located on the hydrophilic surface of SDHA to hinder the entry of substrate (S) into the active site. (B) Acetylation can also alter the access of cytoplasmic substrates to GAPDH by promoting nuclear accumulation of GAPDH. Enzymes, acetylated lysine residues (K), and active sites are labeled as in Fig. 1. N, nucleus; C, cytoplasm.