Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study.

A. Bonifacio, A.R. Groenhof, P.H.J. Keizers, C. de Graaf, J.N.M. Commandeur, N.P.E. Vermeulen, A.W. Ehlers, K. Lammertsma, C. Gooijer, G. van der Zwan

Research output: Contribution to JournalArticleAcademicpeer-review

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. © 2007 SBIC.
Original languageEnglish
Pages (from-to)645-654
JournalJournal of Biological Inorganic Chemistry - JBIC
Volume12
Issue number5
DOIs
Publication statusPublished - 2007

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Cytochrome P-450 CYP2D6
Catalytic Domain
Threonine
Heme
Cytochrome P-450 Enzyme System
Density functional theory
Substitution reactions
Enzymes

Cite this

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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. {\circledC} 2007 SBIC.",
author = "A. Bonifacio and A.R. Groenhof and P.H.J. Keizers and {de Graaf}, C. and J.N.M. Commandeur and N.P.E. Vermeulen and A.W. Ehlers and K. Lammertsma and C. Gooijer and {van der Zwan}, G.",
year = "2007",
doi = "10.1007/s00775-007-0210-5",
language = "English",
volume = "12",
pages = "645--654",
journal = "Journal of Biological Inorganic Chemistry - JBIC",
issn = "0949-8257",
publisher = "Springer Verlag",
number = "5",

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Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study. / Bonifacio, A.; Groenhof, A.R.; Keizers, P.H.J.; de Graaf, C.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Ehlers, A.W.; Lammertsma, K.; Gooijer, C.; van der Zwan, G.

In: Journal of Biological Inorganic Chemistry - JBIC, Vol. 12, No. 5, 2007, p. 645-654.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study.

AU - Bonifacio, A.

AU - Groenhof, A.R.

AU - Keizers, P.H.J.

AU - de Graaf, C.

AU - Commandeur, J.N.M.

AU - Vermeulen, N.P.E.

AU - Ehlers, A.W.

AU - Lammertsma, K.

AU - Gooijer, C.

AU - van der Zwan, G.

PY - 2007

Y1 - 2007

N2 - 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. © 2007 SBIC.

AB - 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. © 2007 SBIC.

U2 - 10.1007/s00775-007-0210-5

DO - 10.1007/s00775-007-0210-5

M3 - Article

VL - 12

SP - 645

EP - 654

JO - Journal of Biological Inorganic Chemistry - JBIC

JF - Journal of Biological Inorganic Chemistry - JBIC

SN - 0949-8257

IS - 5

ER -