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Metabolism of N-substituted 7-methoxy-4-(aminomethyl) -coumarins by cytochrome P450 2D6 mutants and the indication of additional substrate interaction points.
Xenobiotica. 2006 Sep; 36(9):763-71.X

Abstract

Previous studies have shown the critical roles residues F120 and F483 play in the oxidative metabolism of 7-methoxy-4-(aminomethyl)-coumarin (MAMC) by cytochrome P450 2D6 (CYP2D6). In the present study, a series of N-alkyl-7-methoxy-4-(aminomethyl)-coumarins (MAMC analogues) were used as substrates for the F120A and F483A mutants in order to probe the CYP2D6 active site. The F120A and F483A mutants of CYP2D6 displayed significant activity towards the MAMC analogues. Automated docking studies of the MAMC analogues in a CYP2D6 homology model suggested a distal hydrophobic active site binding cleft for the substrate N-alkyl chains, consisting of the residues L213 and V308.

Authors+Show Affiliations

Department of Pharmacochemistry, Division of Molecular Toxicology, Leiden Amsterdam Center for Drug Research (LACDR), Vrije Universiteit, Amsterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16971342

Citation

Keizers, P H J., et al. "Metabolism of N-substituted 7-methoxy-4-(aminomethyl) -coumarins By Cytochrome P450 2D6 Mutants and the Indication of Additional Substrate Interaction Points." Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 36, no. 9, 2006, pp. 763-71.
Keizers PH, Van Dijk BR, De Graaf C, et al. Metabolism of N-substituted 7-methoxy-4-(aminomethyl) -coumarins by cytochrome P450 2D6 mutants and the indication of additional substrate interaction points. Xenobiotica. 2006;36(9):763-71.
Keizers, P. H., Van Dijk, B. R., De Graaf, C., Van Vugt-Lussenburg, B. M., Vermeulen, N. P., & Commandeur, J. N. (2006). Metabolism of N-substituted 7-methoxy-4-(aminomethyl) -coumarins by cytochrome P450 2D6 mutants and the indication of additional substrate interaction points. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 36(9), 763-71.
Keizers PH, et al. Metabolism of N-substituted 7-methoxy-4-(aminomethyl) -coumarins By Cytochrome P450 2D6 Mutants and the Indication of Additional Substrate Interaction Points. Xenobiotica. 2006;36(9):763-71. PubMed PMID: 16971342.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolism of N-substituted 7-methoxy-4-(aminomethyl) -coumarins by cytochrome P450 2D6 mutants and the indication of additional substrate interaction points. AU - Keizers,P H J, AU - Van Dijk,B R, AU - De Graaf,C, AU - Van Vugt-Lussenburg,B M A, AU - Vermeulen,N P E, AU - Commandeur,J N M, PY - 2006/9/15/pubmed PY - 2007/1/27/medline PY - 2006/9/15/entrez SP - 763 EP - 71 JF - Xenobiotica; the fate of foreign compounds in biological systems JO - Xenobiotica VL - 36 IS - 9 N2 - Previous studies have shown the critical roles residues F120 and F483 play in the oxidative metabolism of 7-methoxy-4-(aminomethyl)-coumarin (MAMC) by cytochrome P450 2D6 (CYP2D6). In the present study, a series of N-alkyl-7-methoxy-4-(aminomethyl)-coumarins (MAMC analogues) were used as substrates for the F120A and F483A mutants in order to probe the CYP2D6 active site. The F120A and F483A mutants of CYP2D6 displayed significant activity towards the MAMC analogues. Automated docking studies of the MAMC analogues in a CYP2D6 homology model suggested a distal hydrophobic active site binding cleft for the substrate N-alkyl chains, consisting of the residues L213 and V308. SN - 0049-8254 UR - https://www.unboundmedicine.com/medline/citation/16971342/Metabolism_of_N_substituted_7_methoxy_4__aminomethyl___coumarins_by_cytochrome_P450_2D6_mutants_and_the_indication_of_additional_substrate_interaction_points_ L2 - https://www.tandfonline.com/doi/full/10.1080/00498250600765325 DB - PRIME DP - Unbound Medicine ER -