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Published on: February 15, 2016
Identification of 8-Hydroxyquinoline Derivatives That Decrease Cystathionine Beta Synthase (CBS) Activity
Pierre Conan1, Alice Léon1, Mathilde Gourdel2,3
1Inserm, Université de Brest, EFS, UMR 1078, GGB, 29200 Brest, France.
Abstract:
CBS encodes a pyridoxal 5'-phosphate-dependent enzyme that catalyses the condensation of homocysteine and serine to form cystathionine. Due to its implication in some cancers and in the cognitive pathophysiology of Down syndrome, the identification of pharmacological inhibitors of this enzyme is urgently required. However, thus far, attempts to identify such molecules have only led to the identification of compounds with low potency and limited selectivity. We consequently developed an original, yeast-based screening method that identified three FDA-approved drugs of the 8-hydroxyquinoline family: clioquinol, chloroxine and nitroxoline. These molecules reduce CBS enzymatic activity in different cellular models, proving that the molecular mechanisms involved in yeast phenotypic rescue are conserved in mammalian cells. A combination of genetic and chemical biology approaches also revealed the importance of copper and zinc intracellular levels in the regulation of CBS enzymatic activity-copper promoting CBS activity and zinc inhibiting its activity. Taken together, these results indicate that our effective screening approach identified three new potent CBS inhibitors and provides new findings for the regulation of CBS activity, which is crucial to develop new therapies for CBS-related human disorders.
Insights
Researchers identified three FDA-approved drugs as potent inhibitors of cystathionine beta-synthase (CBS). This discovery offers new therapeutic avenues for cancers and Down syndrome by targeting CBS enzymatic 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.
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