Theoretical Perspective on the Structure and Mechanism of Cytochrome P450 Enzymes

Shaik, Sason; Kumar, Devesh; Visser, Sam P. de; Altun, Ahmet; Thiel, Walter

doi:10.1021/cr030722j

Cited by 1,147 publications

(1,273 citation statements)

References 251 publications

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“…In the crystal structure, the 22R-hydroxyl is located above the heme tetrapyrrole with the Fe-O22 distance (2.56 Å) within the reported errors for a coordinate bond (23), yet, in solution, 22HC elicits a partial type 1 spectral response in the CYP11A1 absolute spectrum and predominantly a type 1 response in the difference spectrum ( Fig. 2), indicative of pentacoordinate iron with no distal coordination.…”

Section: Resultssupporting

confidence: 62%

Structural Basis for Three-step Sequential Catalysis by the Cholesterol Side Chain Cleavage Enzyme CYP11A1

Mast

Annalora

Lodowski

et al. 2011

Journal of Biological Chemistry

125

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Mitochondrial cytochrome P450 11A1 (CYP11A1 or P450 11A1) is the only known enzyme that cleaves the side chain of cholesterol, yielding pregnenolone, the precursor of all steroid hormones. Pregnenolone is formed via three sequential monooxygenation reactions that involve the progressive production of 22R-hydroxycholesterol (22HC) and 20␣,22R-dihydroxycholesterol, followed by the cleavage of the C20-C22 bond. Herein, we present the 2.5-Å crystal structure of CYP11A1 in complex with the first reaction intermediate, 22HC. The active site cavity in CYP11A1 represents a long curved tube that extends from the protein surface to the heme group, the site of catalysis. 22HC occupies two-thirds of the cavity with the 22R-hydroxyl group nearest the heme, 2.56 Å from the iron. The space at the entrance to the active site is not taken up by 22HC but filled with ordered water molecules. The network formed by these water molecules allows the "soft" recognition of the 22HC 3␤-hydroxyl. Such a mode of 22HC binding suggests shuttling of the sterol intermediates between the active site entrance and the heme group during the three-step reaction. Translational freedom of 22HC and torsional motion of its aliphatic tail are supported by solution studies. The CYP11A1-22HC co-complex also provides insight into the structural basis of the strict substrate specificity and high catalytic efficiency of the enzyme and highlights conserved structural motifs involved in redox partner interactions by mitochondrial P450s.

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Section: Resultssupporting

confidence: 62%

Structural Basis for Three-step Sequential Catalysis by the Cholesterol Side Chain Cleavage Enzyme CYP11A1

Mast

Annalora

Lodowski

et al. 2011

Journal of Biological Chemistry

125

View full text Add to dashboard Cite

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“…[15] This compound I then hydroxylates the substrate involving most likely a rebound mechanism (and two-state reactivity). [16] There also exist nonheme iron enzymes in biology that have iron-oxo as the active species, and for which, many biomimetic complexes have been synthesized. [17] Intriguingly, whereas the enzymatic species are high-spin (quintet), most biomimetic complexes have intermediate spin (triplet).…”

Section: Metal-oxo Species and Exchange-enhanced Reactivitymentioning

confidence: 99%

Spin states of (bio)inorganic systems: Successes and pitfalls

Swart

2012

Int J of Quantum Chemistry

112

127

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The calculation of spin-state splittings of transition-metal complexes is known to be very sensitive to the level of theory and the quality of the basis set. The performance of density functionals is in general understood, with older pure functionals overstabilizing low spin states, and Hartree-Fock and hybrid functionals doing the same for the high spin states. More recent functionals (OLYP/OPBE, TPSSh, SSB-D, M06-L) seem to improve on these, but there are still some systems that prove difficult. This Perspective describes some of the recent successes and pitfalls in the description of spin states and treats both methodology and applications such as metal-oxo complexes, exchange-enhanced reactivity, spin-state catalysis, and spin-crossover compounds.

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“…exactly where the shoulder appears in the 266 nm photolysis. Since azide anions from the redox-neutral Fe−N Step-scan FTIR spectra of the quenching experiments with P(nBu) 3 . (e and f) DFT-theoretical spectra for the quenching reaction 5 converting the iron(V)nitride into the phosphoraniminato-iron(III) complex under pseudo-first-order conditions in the presence of the photoreduction channel.…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

“…Along these lines of thoughts, iron(V) nitrides have been shown to act as two-electron nitrogen-atom transfer reagents. 13,18,20 As such they are able to form iron(III) phosphoraniminato complexes upon their bimolecular encounter with phosphorus(III) nucleophiles like tri-n-butylphosphane, P(nBu) 3 , according to…”

Section: Journal Of the American Chemical Societymentioning

confidence: 99%

The Photochemical Route to Octahedral Iron(V). Primary Processes and Quantum Yields from Ultrafast Mid-Infrared Spectroscopy

et al. 2014

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Recently, the complex cation [(cyclam-ac)Fe III (N 3 )] + has been used in solid matrices under cryogenic conditions as a photochemical precursor for an octahedral iron nitride containing the metal at the remarkably high oxidation state +5. Here, we study the photochemical primary events of this complex cation in liquid solution at room temperature using femtosecond time-resolved mid-infrared (fs-MIR) spectroscopy as well as step-scan Fourier-transform infrared spectroscopy, both of which were carried out with variable-wavelength excitation. In stark contrast to the cryomatrix experiments, a photooxidized product cannot be detected in liquid solution when the complex is excited through its putative LMCT band in the visible region. Instead, only a redox-neutral dissociation of azide anions is seen under these conditions. However, clear evidence is found for the formation of the highly oxidized iron nitride product when the photolysis is carried out in liquid solution with UV light. Yet, the photooxidation must compete with photoreductive Fe−N bond cleavage leading to azide radicals and an iron(II) complex. Both, redox-neutral and photoreductive Fe−N bond breakage as well as photooxidative N−N bond breakage occur on a time scale well below a few hundred femtoseconds. The majority of fragments suffer from geminate recombination back to the parent complex on a time scale of 10 ps. Upper limits of the primary quantum yield for photooxidation are derived from the fs-MIR data, which increase with increasing energy of the photolysis photon.

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Theoretical Perspective on the Structure and Mechanism of Cytochrome P450 Enzymes

Cited by 1,147 publications

References 251 publications

Structural Basis for Three-step Sequential Catalysis by the Cholesterol Side Chain Cleavage Enzyme CYP11A1

Structural Basis for Three-step Sequential Catalysis by the Cholesterol Side Chain Cleavage Enzyme CYP11A1

Spin states of (bio)inorganic systems: Successes and pitfalls

The Photochemical Route to Octahedral Iron(V). Primary Processes and Quantum Yields from Ultrafast Mid-Infrared Spectroscopy

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