Structural highlights
Function
[CP2C9_HUMAN] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Publication Abstract from PubMed
Single-nucleotide polymorphisms in drug-metabolizing cytochrome P450 (CYP) enzymes are important contributors to interindividual differences in drug metabolism leading to adverse drug reactions. Despite their extensive characterization and importance in pharmacogenetics of clinical drugs, the structural basis of CYP polymorphisms has remained scant. Here we report the crystal structures of human CYP2C9 and its polymorphic variants, *3 (I359L) and *30 (A477T), with an antihypertensive drug losartan. The structures show distinct interaction and occupation of losartan in the active site, the access channel, and the peripheral binding site. The I359L substitution located far from the active site remarkably altered the residue side chains near the active site and the access channel, whereas the T477 substitution illustrated hydrogen-bonding interaction with the reoriented side chain of Q214. The results yield structural insights into the reduced catalytic activity of the CYP2C9 variants and have important implications for understanding genetic polymorphisms in CYP-mediated drug metabolism.
Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9.,Maekawa K, Adachi M, Matsuzawa Y, Zhang Q, Kuroki R, Saito Y, Shah MB Biochemistry. 2017 Oct 17;56(41):5476-5480. doi: 10.1021/acs.biochem.7b00795., Epub 2017 Oct 3. PMID:28972767[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Maekawa K, Adachi M, Matsuzawa Y, Zhang Q, Kuroki R, Saito Y, Shah MB. Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9. Biochemistry. 2017 Oct 17;56(41):5476-5480. doi: 10.1021/acs.biochem.7b00795., Epub 2017 Oct 3. PMID:28972767 doi:http://dx.doi.org/10.1021/acs.biochem.7b00795
