Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study.
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.
Bonifacio
Alois
A
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.
Groenhof
André R
AR
Keizers
Peter H J
PH
de Graaf
Chris
C
Commandeur
Jan N M
JN
Vermeulen
Nico P E
NP
Ehlers
Andreas W
AW
Lammertsma
Koop
K
Gooijer
Cees
C
van der Zwan
Gert
G
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
D006418:Heme; D019389:Cytochrome P-450 CYP2D6