NDLI: How Is a Metabolic Intermediate Formed in the Mechanism-Based Inactivation of Cytochrome P450 by Using 1,1-Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

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How Is a Metabolic Intermediate Formed in the Mechanism-Based Inactivation of Cytochrome P450 by Using 1,1-Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

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How Is a Metabolic Intermediate Formed in the Mechanism-Based Inactivation of Cytochrome P450 by Using 1,1-Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Chuanprasit, Pratanphorn Hirao, Hajime Cheong, Ying Yi Wang, Xiaoqing
Description	Author Affiliation: Hirao H ( Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371. hirao@ntu.edu.sg)
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 CH bond of the methyl group were found to be less favorable than the hydrogen abstraction from the NH 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.
ISSN	09476539
e-ISSN	15213765
Journal	Chemistry - A European Journal
Issue Number	23
Volume Number	19
Language	English
Publisher	Wiley-VCH;ChemPubSoc Europe
Publisher Date	2013-06-03
Publisher Place	Germany
Access Restriction	Open
Subject Keyword	Cytochrome P-450 Enzyme System Chemistry Metabolism Dimethylhydrazines Heme Nitrogen Catalysis Hydrogen Hydrogen Bonding Oxidation-Reduction Quantum Theory Research Support, Non-U.S. Gov't
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Catalysis

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