Identification of 8-Hydroxyquinoline Derivatives That Decrease Cystathionine Beta Synthase (CBS) Activity.

Area of Science:

• Biochemistry
• Enzymology
• Pharmacology

Background:

• Cystathionine beta-synthase (CBS) is a pyridoxal 5'-phosphate-dependent enzyme crucial for amino acid metabolism.
• CBS dysfunction is implicated in cancers and Down syndrome, necessitating the development of effective inhibitors.
• Previous attempts to find CBS inhibitors yielded compounds with low potency and selectivity.

Purpose of the Study:

• To develop an effective screening method for identifying novel cystathionine beta-synthase (CBS) inhibitors.
• To identify FDA-approved drugs with CBS inhibitory activity.
• To elucidate the role of metal ions in CBS activity regulation.

Main Methods:

• Developed a novel yeast-based screening assay to identify CBS inhibitors.
• Utilized genetic and chemical biology approaches to validate findings.
• Tested identified compounds in various cellular models.

Main Results:

• Identified three FDA-approved 8-hydroxyquinoline drugs (clioquinol, chloroxine, nitroxoline) as potent CBS inhibitors.
• Demonstrated that these inhibitors reduce CBS enzymatic activity in mammalian cells.
• Revealed that copper enhances and zinc inhibits CBS activity.

Conclusions:

• The yeast-based screening method is effective for identifying CBS inhibitors.
• Clioquinol, chloroxine, and nitroxoline represent promising candidates for therapeutic development.
• Intracellular copper and zinc levels are critical regulators of CBS activity, offering new insights for therapeutic strategies.