Photoinduced Covalent Irreversible Inactivation of Proline Dehydrogenase by S-Heterocycles

Area of Science:

• Biochemistry and enzymology
• Medicinal chemistry
• Photopharmacology

Background:

• Proline dehydrogenase (PRODH) is a key enzyme in proline catabolism.
• PRODH is implicated in cancer cell metabolic reprogramming and is a cancer therapy target.
• Targeting PRODH offers a potential strategy for cancer treatment.

Purpose of the Study:

• To discover and characterize a new class of PRODH inactivators.
• To investigate the mechanism of light-dependent covalent modification and inactivation of PRODH.
• To explore the potential of these compounds as photopharmacological agents against cancer.

Main Methods:

• X-ray crystallography was used to determine the structures of enzyme-inhibitor complexes.
• Absorbance spectroscopy and enzyme kinetics were employed to study the inactivation process.
• In vitro assays assessed enzyme activity, inactivation rates, and irreversibility.

Main Results:

• A novel class of PRODH inactivators was identified, functioning as reversible inhibitors in the dark.
• Light exposure triggers decarboxylation and covalent attachment of the inhibitor to the FAD cofactor, leading to irreversible inactivation.
• Blue light preferentially drives the inactivation process, which was demonstrated to be effective in photosensitizing cancer cells.

Conclusions:

• The discovered compounds represent a new class of PRODH inactivators that are activated by light.
• The mechanism involves photoexcitation of FAD, leading to covalent modification and enzyme inactivation.
• These findings open avenues for developing photopharmacological drugs targeting PRODH for cancer therapy.