title: Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study.
abstract: Cytochrome P450 2D6 (CYP2D6) is one of the most important cytochromes P450 in humans. Resonance Raman data from the T309V mutant of CYP2D6 show that the substitution of the conserved I-helix threonine situated in the enzyme's active site perturbs the heme spin equilibrium in favor of the six-coordinated low-spin species. A mechanistic hypothesis is introduced to explain the experimental observations, and its compatibility with the available structural and spectroscopic data is tested using quantum-mechanical density functional theory calculations on active-site models for both the CYP2D6 wild type and the T309V mutant.
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences, Sections of Analytical Chemistry and Applied Spectroscopy (ACAS), Organic and Inorganic Chemistry and Molecular Toxicology, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: Alois
authors.initials: A
authors.lastname: Bonifacio
authors.forename: André R
authors.initials: AR
authors.lastname: Groenhof
authors.forename: Peter H J
authors.initials: PH
authors.lastname: Keizers
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Commandeur
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Ehlers
authors.forename: Koop
authors.initials: K
authors.lastname: Lammertsma
authors.forename: Cees
authors.initials: C
authors.lastname: Gooijer
authors.forename: Gert
authors.initials: G
authors.lastname: van der Zwan
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics; D006418:Heme / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010957:Plasmids / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet; D013059:Spectrum Analysis, Raman
chemical_list: D006418:Heme; D019389:Cytochrome P-450 CYP2D6