Insights into the Structural Determinants of Substrate Binding to Human Cytochromes P450 2C9 and 2C18

Abstract

Xenobiotic metabolizing cytochrome P450 (CYP) enzymes constitute the major enzyme family in drug metabolism with increasing importance in pharmacogenetics, and more recently to pharmacogenomics. The highly polymorphic CYP2C9 metabolizes over 15% of clinical drugs that include ibuprofen, diclofenac, warfarin, losartan, tolbutamide, and glimepiride. Whereas CYP2C18 represents the least characterized enzyme with little information regarding substrates, the active site and the overall structure, despite the high sequence identity (more than 80%) with other human CYP2C subfamily of enzymes. Sequence alignment of CYP2C9 and 2C18 revealed interesting differences in amino acid substitutions, which allowed analysis of the active site of two enzymes of the same subfamily with distinct information regarding substrate specificity. A homology model of CYP2C18 created using the most recent crystal structure of CYP2C9‐losartan complex revealed key residue substitutions that significantly reduced the volume of the active site. In particular, the larger side chain substitutions L113, F201, F237 and N365 in CYP2C18 protrude the active site and play an important role in ligand interaction. Molecular docking studies using a diverse range of CYP2C9 substrates demonstrated remarkably altered orientation in the CYP2C18 active site indicative of differences in substrate preference compared to CYP2C9. The results suggest the active site architecture of CYP2C18 may not allow binding of larger or bulkier substrates as seen with other human CYP2C enzymes. Overall, the analysis of amino acid differences in the active site, the access channel and the recently identified potential substrate recognition site at the periphery provide important insights into the role of distinct side chain substitutions among related CYP enzymes.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.