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Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9.
Keiko Maekawa1,2, Motoyasu Adachi3, Yumiko Matsuzawa2
1Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kodo, Kyotanabe, Kyoto 610-0395, Japan.
Biochemistry
|October 4, 2017
Summary
Genetic variations in cytochrome P450 (CYP) enzymes impact drug metabolism and safety. This study reveals the structural basis of CYP2C9 polymorphisms, explaining altered drug interactions and metabolism.
Area of Science:
- Biochemistry
- Pharmacology
- Structural Biology
Background:
- Single-nucleotide polymorphisms (SNPs) in drug-metabolizing cytochrome P450 (CYP) enzymes cause significant interindividual variability in drug response.
- Understanding the structural basis of these polymorphisms is crucial for predicting and mitigating adverse drug reactions.
Purpose of the Study:
- To elucidate the structural mechanisms underlying the altered drug metabolism associated with common CYP2C9 variants.
- To investigate the interaction of losartan with wild-type CYP2C9 and its polymorphic variants *3 (I359L) and *30 (A477T).
Main Methods:
- X-ray crystallography was employed to determine the high-resolution structures of human CYP2C9, CYP2C9*3, and CYP2C9*30.
- Complex structures with the antihypertensive drug losartan were analyzed to understand drug-enzyme interactions.
Main Results:
- Distinct binding modes and occupations of losartan were observed in the active site, access channel, and peripheral site of CYP2C9 and its variants.
- The I359L substitution significantly altered the enzyme's active site and access channel residues, despite its distant location.
- The A477T substitution formed hydrogen bonds with a reoriented glutamine residue (Q214).
Conclusions:
- The observed structural changes provide a molecular basis for the reduced catalytic activity of CYP2C9*3 and CYP2C9*30 variants.
- These findings enhance our understanding of genetic polymorphisms in CYP-mediated drug metabolism and have implications for personalized medicine.
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