Expanding the Toolkit for the Serine Hydrolases

Area of Science:

• Biochemistry
• Chemical Biology
• Enzymology

Background:

• Serine hydrolases are a large and diverse enzyme superfamily with critical roles in various biological processes.
• Palmitoyl protein thioesterase 1 (PPT1) and alpha, beta-hydrolase domain-4 (ABHD4) are key members of this superfamily, implicated in diseases such as neuronal ceroid lipofuscinosis.

Purpose of the Study:

• To develop novel pharmacological tools for the study of palmitoyl protein thioesterase 1 (PPT1) and alpha, beta-hydrolase domain-4 (ABHD4).
• To expand the available chemical toolkit for investigating the function and inhibition of serine hydrolases.

Main Methods:

• Synthesis and characterization of N-hydroxyhydantoin-containing carbamate inhibitors.
• Design and application of an activity-based probe for target engagement studies.

Main Results:

• The developed carbamate inhibitors effectively target PPT1 and ABHD4.
• The activity-based probe successfully identified and labeled active PPT1 and ABHD4 enzymes.
• These tools provide new avenues for exploring the biological roles of PPT1 and ABHD4.

Conclusions:

• The new inhibitors and activity-based probe represent valuable additions to the chemical biology toolkit for serine hydrolase research.
• These tools will facilitate further investigation into the physiological and pathological functions of PPT1 and ABHD4.
• This work advances the understanding of enzyme mechanisms and potential therapeutic strategies involving serine hydrolases.