Cytochrome P450 F‐helix N204H mutation in CYP2C9.57 genetic variant reveals non‐typical ligand binding properties.
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| Title: | Cytochrome P450 F‐helix N204H mutation in CYP2C9.57 genetic variant reveals non‐typical ligand binding properties. |
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| Authors: | Kisel, Maryia1 (AUTHOR) marusen.kee@gmail.com, Shapira, Michail1 (AUTHOR), Gilep, Andrei1 (AUTHOR) |
| Source: | FEBS Letters. Dec2025, Vol. 599 Issue 23, p3501-3523. 23p. |
| Subjects: | Drug metabolism, Ligand binding (Biochemistry), Genetic variation, Cytochrome P-450 CYP2C19, Genetic mutation, Individualized medicine, Cytochrome P-450, Pharmacokinetics |
| Abstract: | Genetic variants of various cytochrome P450 (CYP) enzymes significantly impact pharmacokinetics. The highly polymorphic hepatic CYP2C9 metabolizes ~ 15% of clinically used drugs. This study aimed to characterize the ligand‐binding properties of the understudied CYP2C9.57 variant (N204H mutation located in the active site) using spectrophotometric titration with diverse ligands. Type I ligands (diclofenac, tamoxifen) produced unusual reverse type II spectral responses (λmax ~ 410 nm and λmin 430–437 nm), while diclofenac, cyproconazole, and fluconazole showed spectral transitions suggesting dual binding modes. Unlike the wild‐type protein, the N204H mutation significantly altered ligand binding behavior. A weak cooperative effect (with the Hill coefficients ranging from 0.93 to 2.08) was observed across compounds and isoforms. The N204H mutation in the F/G region likely reduces active site cavity volume, with His204 forming additional contacts that appear to restrict ligand access to the heme iron. These findings provide insights for predicting altered drug metabolism, supporting personalized medicine. Impact statementThis study provides fundamental insights into the impact of genetic polymorphisms on CYP2C9 enzyme function, specifically the N204H mutation. By revealing alterations in ligand binding behavior and structural changes within the F/G region, these findings contribute to a deeper understanding of pharmacokinetics and may aid future advancements in drug discovery. [ABSTRACT FROM AUTHOR] |
| Copyright of FEBS Letters is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Cytochrome P450 F‐helix N204H mutation in CYP2C9.57 genetic variant reveals non‐typical ligand binding properties. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Kisel%2C+Maryia%22">Kisel, Maryia</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> marusen.kee@gmail.com</i><br /><searchLink fieldCode="AR" term="%22Shapira%2C+Michail%22">Shapira, Michail</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gilep%2C+Andrei%22">Gilep, Andrei</searchLink><relatesTo>1</relatesTo> (AUTHOR) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22FEBS+Letters%22">FEBS Letters</searchLink>. Dec2025, Vol. 599 Issue 23, p3501-3523. 23p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Drug+metabolism%22">Drug metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Ligand+binding+%28Biochemistry%29%22">Ligand binding (Biochemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+variation%22">Genetic variation</searchLink><br /><searchLink fieldCode="DE" term="%22Cytochrome+P-450+CYP2C19%22">Cytochrome P-450 CYP2C19</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+mutation%22">Genetic mutation</searchLink><br /><searchLink fieldCode="DE" term="%22Individualized+medicine%22">Individualized medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Cytochrome+P-450%22">Cytochrome P-450</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacokinetics%22">Pharmacokinetics</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Genetic variants of various cytochrome P450 (CYP) enzymes significantly impact pharmacokinetics. The highly polymorphic hepatic CYP2C9 metabolizes ~ 15% of clinically used drugs. This study aimed to characterize the ligand‐binding properties of the understudied CYP2C9.57 variant (N204H mutation located in the active site) using spectrophotometric titration with diverse ligands. Type I ligands (diclofenac, tamoxifen) produced unusual reverse type II spectral responses (λmax ~ 410 nm and λmin 430–437 nm), while diclofenac, cyproconazole, and fluconazole showed spectral transitions suggesting dual binding modes. Unlike the wild‐type protein, the N204H mutation significantly altered ligand binding behavior. A weak cooperative effect (with the Hill coefficients ranging from 0.93 to 2.08) was observed across compounds and isoforms. The N204H mutation in the F/G region likely reduces active site cavity volume, with His204 forming additional contacts that appear to restrict ligand access to the heme iron. These findings provide insights for predicting altered drug metabolism, supporting personalized medicine. Impact statementThis study provides fundamental insights into the impact of genetic polymorphisms on CYP2C9 enzyme function, specifically the N204H mutation. By revealing alterations in ligand binding behavior and structural changes within the F/G region, these findings contribute to a deeper understanding of pharmacokinetics and may aid future advancements in drug discovery. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of FEBS Letters is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1002/1873-3468.70159 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 23 StartPage: 3501 Subjects: – SubjectFull: Drug metabolism Type: general – SubjectFull: Ligand binding (Biochemistry) Type: general – SubjectFull: Genetic variation Type: general – SubjectFull: Cytochrome P-450 CYP2C19 Type: general – SubjectFull: Genetic mutation Type: general – SubjectFull: Individualized medicine Type: general – SubjectFull: Cytochrome P-450 Type: general – SubjectFull: Pharmacokinetics Type: general Titles: – TitleFull: Cytochrome P450 F‐helix N204H mutation in CYP2C9.57 genetic variant reveals non‐typical ligand binding properties. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Kisel, Maryia – PersonEntity: Name: NameFull: Shapira, Michail – PersonEntity: Name: NameFull: Gilep, Andrei IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 12 Text: Dec2025 Type: published Y: 2025 Identifiers: – Type: issn-print Value: 00145793 Numbering: – Type: volume Value: 599 – Type: issue Value: 23 Titles: – TitleFull: FEBS Letters Type: main |
| ResultId | 1 |
