Distribution and diversity of classical deacylases in bacteria

Area of Science:

• Biochemistry
• Structural Biology
• Microbiology

Background:

• Classical Zn2+-dependent deacylases are crucial in eukaryotes but poorly understood in bacteria.
• Thousands of uncharacterized bacterial deacylases exist, necessitating systematic investigation.

Purpose of the Study:

• To systematically characterize bacterial deacylases, including their structure, function, and substrate specificity.
• To explore potential therapeutic strategies targeting bacterial deacylases.

Main Methods:

• Construction of a Generalized Profile (GP) to identify bacterial deacylases.
• Structural and functional characterization of representative enzymes from five identified clusters.
• X-ray crystallography to determine enzyme-inhibitor co-crystal structures.

Main Results:

• Identification and clustering of thousands of bacterial deacylases.
• Discovery of diverse deacylase functions, including polyamine and protein deacylation with varied acyl-chain preferences.
• Elucidation of structural basis for substrate selectivity and discovery of novel de-D-/L-lactylases and long-chain deacylases.
• Demonstration of inhibition of bacterial deacylases by HDAC inhibitors (SAHA, TSA) via co-crystal structures.

Conclusions:

• Bacterial deacylases exhibit significant functional and structural diversity.
• Understanding substrate specificity and inhibition mechanisms provides a foundation for drug development.
• HDAC inhibitors show promise for repurposing against bacterial infections.