Role of P34S, G169R, R296C, and S486T Substitutions in Ligand Access and Catalysis for Cytochrome P450 2D6 Allelic Variants CYP2D6*14A and CYP2D6*14B
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND: Genetic polymorphism of cytochrome P450 (CYP) contributes to variability in drug metabolism, clearance, and response. This study aimed to investigate the functional and molecular basis for altered ligand binding and catalysis in CYP2D6*14A and CYP2D6*14B, two unique alleles common in the Asian population.
METHODS: CYP proteins expressed in Escherichia coli were studied using the substrate 3-cyano-7- ethoxycoumarin (CEC) and inhibitor probes (quinidine, fluoxetine, paroxetine, terbinafine) in the enzyme assay. Computer modelling was additionally used to create three-dimensional structures of the CYP2D6*14 variants.
RESULTS: Kinetics data indicated significantly reduced intrinsic clearance in CYP2D6*14 variants, suggesting that P34S, G169R, R296C, and S486T substitutions worked cooperatively to alter the conformation of the active site that negatively impacted the deethylase activity of CYP2D6. For the inhibition studies, IC50 values decreased in quinidine, paroxetine, and terbinafine but increased in fluoxetine, suggesting a varied ligand-specific susceptibility to inhibition. Molecular docking further demonstrated the role of P34S and R296C in altering access channel dimensions, thereby affecting ligand access and binding and subsequently resulting in varied inhibition potencies.
CONCLUSION: In summary, the differential selectivity of CYP2D6*14 variants for the ligands (substrate and inhibitor) was governed by the alteration of the active site and access channel architecture induced by the natural mutations found in the alleles.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Drug metabolism and bioanalysis letters - 15(2022), 1 vom: 31., Seite 51-63 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dong, Amelia Nathania [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 18.08.2022 Date Revised 21.12.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.2174/1872312815666220113125232 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM335840981 |
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| 100 | 1 | |a Dong, Amelia Nathania |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Role of P34S, G169R, R296C, and S486T Substitutions in Ligand Access and Catalysis for Cytochrome P450 2D6 Allelic Variants CYP2D6*14A and CYP2D6*14B |
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| 500 | |a Date Completed 18.08.2022 | ||
| 500 | |a Date Revised 21.12.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND: Genetic polymorphism of cytochrome P450 (CYP) contributes to variability in drug metabolism, clearance, and response. This study aimed to investigate the functional and molecular basis for altered ligand binding and catalysis in CYP2D6*14A and CYP2D6*14B, two unique alleles common in the Asian population | ||
| 520 | |a METHODS: CYP proteins expressed in Escherichia coli were studied using the substrate 3-cyano-7- ethoxycoumarin (CEC) and inhibitor probes (quinidine, fluoxetine, paroxetine, terbinafine) in the enzyme assay. Computer modelling was additionally used to create three-dimensional structures of the CYP2D6*14 variants | ||
| 520 | |a RESULTS: Kinetics data indicated significantly reduced intrinsic clearance in CYP2D6*14 variants, suggesting that P34S, G169R, R296C, and S486T substitutions worked cooperatively to alter the conformation of the active site that negatively impacted the deethylase activity of CYP2D6. For the inhibition studies, IC50 values decreased in quinidine, paroxetine, and terbinafine but increased in fluoxetine, suggesting a varied ligand-specific susceptibility to inhibition. Molecular docking further demonstrated the role of P34S and R296C in altering access channel dimensions, thereby affecting ligand access and binding and subsequently resulting in varied inhibition potencies | ||
| 520 | |a CONCLUSION: In summary, the differential selectivity of CYP2D6*14 variants for the ligands (substrate and inhibitor) was governed by the alteration of the active site and access channel architecture induced by the natural mutations found in the alleles | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CYP2D6*14 | |
| 650 | 4 | |a Cytochrome P450 | |
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| 700 | 1 | |a Yiap, Beow Chin |e verfasserin |4 aut | |
| 700 | 1 | |a Ong, Chin Eng |e verfasserin |4 aut | |
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