Site-Selective Phosphoglycerate Mutase 1 Acetylation by a Small Molecule.

Area of Science:

• Biochemistry
• Molecular Biology
• Enzymology

Background:

• Post-translational modifications, particularly acetylation, are crucial for regulating physiological processes.
• Enzyme activity can be modulated through targeted modifications, impacting cellular functions.

Purpose of the Study:

• To develop a ligand-directed method for site-selective acetylation of phosphoglycerate mutase 1 (PGAM1).
• To investigate the mechanism of acetyl group transfer and its physiological consequences.

Main Methods:

• Utilized KHAc, a phosphoglycerate mutase 1 (PGAM1) inhibitor derivative, for targeted acetylation.
• Employed time-resolved crystallography to visualize the acetyl transfer process.
• Assessed the effects of KHAc-mediated acetylation in cultured human cells.

Main Results:

• KHAc selectively acetylates Lys100 of PGAM1, leading to enzyme inactivation.
• Time-resolved crystallography revealed that proximity effects drive the acetyl transfer.
• Site-selective acetylation of PGAM1 by KHAc inhibited F-actin formation in human cells.

Conclusions:

• Ligand-directed acetylation provides a powerful strategy for precise control of enzyme activity.
• This approach offers a potential method for exogenous control of lysine post-translational modifications.
• The findings open avenues for developing novel therapeutic strategies targeting enzyme acetylation.