| Metabolism of N-methyl-amide by cytochrome P450s: formation and characterization of highly stable carbinol-amide intermediate. | |
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MedLine Citation:
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PMID: 21518254 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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We report an unambiguous proof of the stability of a carbinol intermediate in the case P450 metabolism of an N-methylated natural cyclo-peptide, namely tentoxin. Under mild acidic or neutral conditions lifetime of carbinol-amide is long enough to be fully characterized. This metabolite has been characterized using specifically labeled (14) C-methyl tentoxin isotopomers, HPLC, HPLC-MS, MS-MS and NMR. Under stronger acidic conditions, the stability of this metabolite vanishes through deformylation. A theoretical mechanistic investigation reveals that the stability is governed by the accessibility of the nitrogen lone pair and its protonation state. For carbinol amines, even in neutral conditions, the energy barrier for deformylation is low enough to allow rapid deformylation. Carbinol-amide behaves differently. Under neutral condition, delocalization of the nitrogen lone pair increase the energy barrier of deformylation that is a slow process under such conditions. After protonation, we were able to optimize a deformylation transition that is lower in energy and that thus accounts for the lower stability of carbinolamides observed experimentally in acidic conditions. Finally, by considering the protocol usually used for extraction and analysis of this type of metabolite, carbinol-amide may thus be frequently ignored in drug metabolism pathway. |
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Authors:
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Lionel Perrin; Nicolas Loiseau; François André; Marcel Delaforge |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-22 |
Journal Detail:
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Title: The FEBS journal Volume: - ISSN: 1742-4658 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101229646 Medline TA: FEBS J Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Journal compilation © 2011 Federation of European Biochemical Societies. |
Affiliation:
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Université de Toulouse; INSA, UPS; LPCNO (IRSAMC); 135 avenue de Rangueil, F-31077 Toulouse, France and CNRS; UMR 5215 (IRSAMC); F-31077 Toulouse, France CEA, iBiTecS, Service de Bioénergétique Biologie Structurale et Mécanismes (SB2SM), CEA Saclay F-91191 Gif-sur-Yvette, France; and CNRS, URA 2096, F-91191 Gif-Sur-Yvette, France Département de Pharmacologie, Laboratoire de Pharmacologie-Toxicologie INRA, 180 Chemin de Tournefeuille, F31931 Toulouse, France. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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