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Published on: July 4, 2016
Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study
Alois Bonifacio1, André R Groenhof, Peter H J Keizers
1Department 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.
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.
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