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

Alois Bonifacio; André R. Groenhof; Peter H.J. Keizers; Chris De Graaf; Jan N.M. Commandeur; Nico P.E. Vermeulen; Andreas W. Ehlers; Koop Lammertsma; Cees Gooijer; Gert Van Der Zwan

doi:10.1007/s00775-007-0210-5

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

Alois Bonifacio, André R. Groenhof, Peter H.J. Keizers, Chris De Graaf, Jan N.M. Commandeur, Nico P.E. Vermeulen, Andreas W. Ehlers, Koop Lammertsma, Cees Gooijer, Gert Van Der Zwan

Vrije Universiteit Amsterdam

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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.

Original language	English
Pages (from-to)	645-654
Number of pages	10
Journal	Journal of Biological Inorganic Chemistry
Volume	12
Issue number	5
DOIs	https://doi.org/10.1007/s00775-007-0210-5
Publication status	Published - Jun 2007
Externally published	Yes

Keywords

Cytochrome P450 2D6
Resonance Raman
Spin equilibrium
T309V
Threonine mutant

ASJC Scopus subject areas

Biochemistry
Inorganic Chemistry

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10.1007/s00775-007-0210-5

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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. (2007). Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: A spectroscopic and computational study. Journal of Biological Inorganic Chemistry, 12(5), 645-654. https://doi.org/10.1007/s00775-007-0210-5

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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.",

keywords = "Cytochrome P450 2D6, Resonance Raman, Spin equilibrium, T309V, Threonine mutant",

author = "Alois Bonifacio and Groenhof, {Andr{\'e} R.} and Keizers, {Peter H.J.} and {De Graaf}, Chris and Commandeur, {Jan N.M.} and Vermeulen, {Nico P.E.} and Ehlers, {Andreas W.} and Koop Lammertsma and Cees Gooijer and {Van Der Zwan}, Gert",

year = "2007",

month = jun,

doi = "10.1007/s00775-007-0210-5",

language = "English",

volume = "12",

pages = "645--654",

journal = "Journal of Biological Inorganic Chemistry",

issn = "0949-8257",

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Bonifacio, A, Groenhof, AR, Keizers, PHJ, De Graaf, C, Commandeur, JNM, Vermeulen, NPE, Ehlers, AW, Lammertsma, K, Gooijer, C & Van Der Zwan, G 2007, 'Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: A spectroscopic and computational study', Journal of Biological Inorganic Chemistry, vol. 12, no. 5, pp. 645-654. https://doi.org/10.1007/s00775-007-0210-5

TY - JOUR

T1 - Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6

T2 - A spectroscopic and computational study

AU - Bonifacio, Alois

AU - Groenhof, André R.

AU - Keizers, Peter H.J.

AU - De Graaf, Chris

AU - Commandeur, Jan N.M.

AU - Vermeulen, Nico P.E.

AU - Ehlers, Andreas W.

AU - Lammertsma, Koop

AU - Gooijer, Cees

AU - Van Der Zwan, Gert

PY - 2007/6

Y1 - 2007/6

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.

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.

KW - Cytochrome P450 2D6

KW - Resonance Raman

KW - Spin equilibrium

KW - T309V

KW - Threonine mutant

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M3 - Article

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AN - SCOPUS:34249883045

SN - 0949-8257

VL - 12

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EP - 654

JO - Journal of Biological Inorganic Chemistry

JF - Journal of Biological Inorganic Chemistry

IS - 5

ER -

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

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Keywords

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