Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/102396
Title: How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation?
Authors: Hirao, Hajime
Chuanprasit, Pratanphorn
Cheong, Ying Yi
Wang, Xiaoqing
Keywords: DRNTU::Science::Chemistry::Physical chemistry::Catalysis
Issue Date: 2013
Source: Hirao, H., Chuanprasit, P., Cheong, Y. Y., & Wang, X. (2013). How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation?. Chemistry - A European Journal, 19(23), 7361-7369.
Series/Report no.: Chemistry - a European journal
Abstract: A precise understanding of the mechanism-based inactivation of cytochrome P450 enzymes (P450s) at the quantum mechanical level should allow more reliable predictions of drug–drug interactions than those currently available. Hydrazines are among the molecules that act as mechanism-based inactivators to terminate the function of P450s, which are essential heme enzymes responsible for drug metabolism in the human body. Despite its importance, the mechanism explaining how a metabolic intermediate (MI) is formed from hydrazine is not fully understood. We used density functional theory (DFT) calculations to compare four possible mechanisms underlying the reaction between 1,1-dimethylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) and the reactive compound I (Cpd I) intermediate of P450. Our DFT calculations provided a clear view on how an aminonitrene-type MI is formed from UDMH. In the most favorable pathway, hydrogen is spontaneously abstracted from the N2 atom of UDMH by Cpd I, followed by a second hydrogen abstraction from the N2 atom by Cpd II. Nitrogen oxidation of nitrogen atoms and hydrogen abstraction from the C[BOND]H bond of the methyl group were found to be less favorable than the hydrogen abstraction from the N[BOND]H bond. We also found that the reaction of protonated UDMH with Cpd I is rather sluggish. The aminonitrene-type MI binds to the ferric heme more strongly than a water molecule. This is consistent with the notion that the catalytic cycle of P450 is impeded when such an MI is produced through the P450-catalyzed reaction.
URI: https://hdl.handle.net/10356/102396
http://hdl.handle.net/10220/19082
ISSN: 0947-6539
DOI: 10.1002/chem.201300689
Rights: © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SPMS Journal Articles

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.