Binding of bufuralol, dextromethorphan, and 3,4-methylenedioxymethylamphetamine to wild-type and F120A mutant cytochrome P450 2D6 studied by resonance Raman spectroscopy

作者：Bonifacio A; Keizers PHJ; Commandeur JNM; Vermeulen NPE; Robert B; Gooijer C; van der Zwan G^*

来源：Biochemical and Biophysical Research Communications, 2006, 343(3): 772-779.

DOI：10.1016/j.bbrc.2006.03.027

• cytochrome P450 2D6
• CYP2D6
• resonance Raman
• MDMA
• dextromethorphan
• bufuralol
• substrate mobility

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 Phe(120) 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 Phe(120) in binding dextromethorphan and MDMA.

• 出版日期2006-5-12
• 单位中国地震局