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Interaction of Mechanism‐Based Inactivators with Modified CYP2D6
Author(s) -
Livezey Mara R.,
Hicks Michael J.,
Furge Laura Lowe
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1007.3
Subject(s) - cyp2d6 , electrophile , chemistry , stereochemistry , mechanism (biology) , molecular model , cytochrome p450 , tricyclic , lead compound , biochemistry , enzyme , in vitro , philosophy , epistemology , catalysis
Mechanism‐based inactivators lead to covalent adduction of CYPs. There are a few known inactivators of CYP2D6 including two confirmed protein adductors – SCH66712 and EMTPP, and some heme modifiers including paroxetine and MDMA. To understand the potential similarities and differences between these classes of inactivators, we have used molecular modeling to analyze types of interactions that might lead to inactivation. From our modeling experiments we predicted Thr309 of CYP2D6 to be a likely nucleophilic target of the electrophiles formed from the protein inactivators. Isolation of the CYP2D6‐SCH66712 inhibitory complex allowed us to confirm Thr309 as a putative electrophilic target. Two other potential target residues were also identified. We have mutated these residues to Ala to test for interaction with the different classes of inactivators and will present data on the altered kinetics of interaction of mutant CYP2D6 with known mechanism‐based inactivators. (Support: NIH 1R15‐GM086767–01 & ‐01S1)