How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation?
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...
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| Format: | Journal Article |
| Language: | English |
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2014
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| Online Access: | https://hdl.handle.net/10356/102396 http://hdl.handle.net/10220/19082 |
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| author | Hirao, Hajime Chuanprasit, Pratanphorn Cheong, Ying Yi Wang, Xiaoqing |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Hirao, Hajime Chuanprasit, Pratanphorn Cheong, Ying Yi Wang, Xiaoqing |
| author_sort | Hirao, Hajime |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T07:02:51Z |
| format | Journal Article |
| id | ntu-10356/102396 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:02:51Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | ntu-10356/1023962020-03-07T12:34:51Z How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation? Hirao, Hajime Chuanprasit, Pratanphorn Cheong, Ying Yi Wang, Xiaoqing School of Physical and Mathematical Sciences DRNTU::Science::Chemistry::Physical chemistry::Catalysis 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. 2014-04-03T06:21:18Z 2019-12-06T20:54:16Z 2014-04-03T06:21:18Z 2019-12-06T20:54:16Z 2013 2013 Journal Article 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. 0947-6539 https://hdl.handle.net/10356/102396 http://hdl.handle.net/10220/19082 10.1002/chem.201300689 en Chemistry - a European journal © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
| spellingShingle | DRNTU::Science::Chemistry::Physical chemistry::Catalysis Hirao, Hajime Chuanprasit, Pratanphorn Cheong, Ying Yi Wang, Xiaoqing How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation? |
| 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? |
| title_full | How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation? |
| title_fullStr | How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation? |
| title_full_unstemmed | How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation? |
| title_short | How Is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine : hydrogen abstraction or nitrogen oxidation? |
| title_sort | how is a metabolic intermediate formed in the mechanism based inactivation of cytochrome p450 by using 1 1 dimethylhydrazine hydrogen abstraction or nitrogen oxidation |
| topic | DRNTU::Science::Chemistry::Physical chemistry::Catalysis |
| url | https://hdl.handle.net/10356/102396 http://hdl.handle.net/10220/19082 |
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