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Binding of bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine to wild-type and F120A mutant cytochrome P450 2D6 studied by resonance Raman spectroscopy.
Biochem Biophys Res Commun. 2006 May 12; 343(3):772-9.BB

Abstract

Cytochrome P450 2D6 (CYP2D6) is one of the most important drug-metabolizing enzymes in humans. Resonance Raman data, reported for the first time for CYP2D6, show that the CYP2D6 heme is found to be in a six-coordinated low-spin state in the absence of substrates, and it is perturbed to different extents by bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine (MDMA). Dextromethorphan and MDMA induce in CYP2D6 a significant amount of five-coordinated high-spin heme species and reduce the polarity of its heme-pocket, whereas bufuralol does not. Spectra of the F120A mutant CYP2D6 suggest that Phe120 is involved in substrate-binding of dextromethorphan and MDMA, being responsible for the spectral differences observed between these two compounds and bufuralol. These differences could be explained postulating a different substrate mobility for each compound in the CYP2D6 active site, consistently with the role previously suggested for Phe120 in binding dextromethorphan and MDMA.

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Authors+Show Affiliations

Bonifacio A
Laser Centre/Analytical Chemistry and Applied Spectroscopy, Vrije Universiteit Amsterdam, The Netherlands.
Keizers PH
No affiliation info available
Commandeur JN
No affiliation info available
Vermeulen NP
No affiliation info available
Robert B
No affiliation info available
Gooijer C
No affiliation info available
van der Zwan G
No affiliation info available

MeSH

Amino Acid SubstitutionBinding SitesCytochrome P-450 CYP2D6DextromethorphanEthanolaminesHemeHumansMutationN-Methyl-3,4-methylenedioxyamphetamineSpectrum Analysis, Raman

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16563352

Citation

Bonifacio, Alois, et al. "Binding of Bufuralol, Dextromethorphan, and 3,4-methylenedioxymethylamphetamine to Wild-type and F120A Mutant Cytochrome P450 2D6 Studied By Resonance Raman Spectroscopy." Biochemical and Biophysical Research Communications, vol. 343, no. 3, 2006, pp. 772-9.
Bonifacio A, Keizers PH, Commandeur JN, et al. Binding of bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine to wild-type and F120A mutant cytochrome P450 2D6 studied by resonance Raman spectroscopy. Biochem Biophys Res Commun. 2006;343(3):772-9.
Bonifacio, A., Keizers, P. H., Commandeur, J. N., Vermeulen, N. P., Robert, B., Gooijer, C., & van der Zwan, G. (2006). Binding of bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine to wild-type and F120A mutant cytochrome P450 2D6 studied by resonance Raman spectroscopy. Biochemical and Biophysical Research Communications, 343(3), 772-9.
Bonifacio A, et al. Binding of Bufuralol, Dextromethorphan, and 3,4-methylenedioxymethylamphetamine to Wild-type and F120A Mutant Cytochrome P450 2D6 Studied By Resonance Raman Spectroscopy. Biochem Biophys Res Commun. 2006 May 12;343(3):772-9. PubMed PMID: 16563352.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Binding of bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine to wild-type and F120A mutant cytochrome P450 2D6 studied by resonance Raman spectroscopy. AU - Bonifacio,Alois, AU - Keizers,Peter H J, AU - Commandeur,Jan N M, AU - Vermeulen,Nico P E, AU - Robert,Bruno, AU - Gooijer,Cees, AU - van der Zwan,Gert, Y1 - 2006/03/20/ PY - 2006/03/06/received PY - 2006/03/07/accepted PY - 2006/3/28/pubmed PY - 2006/5/25/medline PY - 2006/3/28/entrez SP - 772 EP - 9 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 343 IS - 3 N2 - Cytochrome P450 2D6 (CYP2D6) is one of the most important drug-metabolizing enzymes in humans. Resonance Raman data, reported for the first time for CYP2D6, show that the CYP2D6 heme is found to be in a six-coordinated low-spin state in the absence of substrates, and it is perturbed to different extents by bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine (MDMA). Dextromethorphan and MDMA induce in CYP2D6 a significant amount of five-coordinated high-spin heme species and reduce the polarity of its heme-pocket, whereas bufuralol does not. Spectra of the F120A mutant CYP2D6 suggest that Phe120 is involved in substrate-binding of dextromethorphan and MDMA, being responsible for the spectral differences observed between these two compounds and bufuralol. These differences could be explained postulating a different substrate mobility for each compound in the CYP2D6 active site, consistently with the role previously suggested for Phe120 in binding dextromethorphan and MDMA. SN - 0006-291X UR - https://www.unboundmedicine.com/medline/citation/16563352/Binding_of_bufuralol_dextromethorphan_and_34_methylenedioxymethylamphetamine_to_wild_type_and_F120A_mutant_cytochrome_P450_2D6_studied_by_resonance_Raman_spectroscopy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(06)00550-X DB - PRIME DP - Unbound Medicine ER -