CYP2J5 Inhibitors

Chemical inhibitors of CYP2J5 can be understood through the molecular interactions that impede the enzyme's normal metabolic functions. Miconazole, Ketoconazole, Fluconazole, Sulconazole, Clotrimazole, Econazole, Tioconazole, Voriconazole, Isavuconazole, and Posaconazole all share a common mechanism of action in which they bind to the heme iron within the active site of CYP2J5. This binding event is crucial because the heme iron is central to the enzyme's ability to catalyze metabolic reactions. By occupying this site, these chemicals effectively prevent the access of substrate molecules to the catalytic iron ion, thereby inhibiting the metabolic activity that CYP2J5 would typically perform. The binding is not merely a passive blockage; it involves a coordination to the heme group, which is a deliberate interference with the enzyme's catalytic machinery. This action ensures that the enzyme is unable to process its normal substrates, which in turn inhibits its function.

The influence of Terbinafine and Sertraline on CYP2J5 involves a different approach that still results in functional inhibition of the enzyme. Terbinafine inhibits squalene epoxidase, an enzyme upstream in the ergosterol synthesis pathway, leading to a decrease in ergosterol synthesis. Ergosterol is a substrate necessary for certain metabolic pathways, including those in which CYP2J5 is involved. By reducing the availability of ergosterol, Terbinafine indirectly inhibits the functioning of CYP2J5 by limiting the substrate availability required for its activity. On the other hand, Sertraline binds directly to CYP2J5, inducing a conformational change in the enzyme. This alteration not only hampers the binding of natural substrates but also hinders the enzymatic activity of CYP2J5. The conformational change is akin to a lock being jammed, thus preventing the normal operation of the enzyme. The direct binding by Sertraline can lead to a reduction in the enzyme's ability to metabolize its substrates, which constitutes an inhibition of CYP2J5's normal function.