Mechanism-based inactivation of cytochromes by furan epoxide: unraveling the molecular mechanism.
Drugs carrying an unsaturated C═C center (such as furans) form reactive epoxide metabolites and cause irreversible mechanism-based inactivation (MBI) of cytochrome P450 (CYP450) activity, through covalent modification of amino acid residues. Though this reaction is confirmed to take place in the active site of CYPs, the details of the reactions of furan (epoxidation and epoxide ring opening), the conditions under which MBI may occur, the residues involved, the importance of the heme center, etc. have yet to be explored. A density functional theory (DFT) study was carried out (i) to elucidate the reaction pathways for the generation of furan epoxide metabolite from furan ring by the model oxidant Cpd I (iron(IV)-oxo heme-porphine radical cation, to mimic the catalytic domain of CYPs) and (ii) to explore different reactions of the furan epoxide metabolite. The energy profiles of the competitive pathways and the conditions facilitating MBI of CYPs by the reactive epoxide metabolite are reported. The rate-determining step for the overall metabolic pathway leading to MBI was observed to be the initial epoxidation, requiring ∼12 kcal/mol under the enzymatic conditions. The covalent adducts (inactivator complexes) are highly stable (∼-46 to -70 kcal/mol) and may be formed due to the reaction between furan epoxide and nucleophilic amino acid residues such as serine/threonine, preferably after initial activation by basic amino acids.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, S. A. S. Nagar (Mohali), 160 062 Punjab, India.
Nikhil
N
Taxak
Sourav
S
Kalra
Prasad V
PV
Bharatam
D020134:Catalytic Domain; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006868:Hydrolysis; D008958:Models, Molecular; D011789:Quantum Theory; D014867:Water / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005663:Furans; D014867:Water; D003577:Cytochrome P-450 Enzyme System; C039281:furan