Cytochrome P450 Compound I: Capture, Characterization, and C-H Bond Activation Kinetics

  title={Cytochrome P450 Compound I: Capture, Characterization, and C-H Bond Activation Kinetics},
  author={Jonathan Rittle and Michael T. Green},
  pages={933 - 937}
The Power Behind P450 Drugs, toxins and a range of metabolic substrates are detoxified in the liver by family of iron-containing enzymes called cytochrome P450. The iron component transfers oxygen to compounds that are often highly resistant to chemical reaction, but we know very little about the mechanism of this vital detoxification process. Rittle and Green (p. 933; see the Perspective by Sligar) have managed to capture the P450 reaction intermediate by freezing a solution of the enzyme as… 
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It is demonstrated that the generation and reactivity of oxo-iron reactive intermediates derived from even simple or structurally remote cytochrome P450 mimics can be tuned to that observed for native enzymes through the selection of appropriate reaction conditions.
Mechanisms of Cytochrome P450-Catalyzed Oxidations.
Current P450 questions under investigation include the potential role of the intermediate Compound 0 (formally FeIII-O2 -) in catalysis of some reactions, the roles of high- and low-spin forms of Compound I, the mechanism of desaturation, the role of open and closed structures of P450s inCatalysis, the extent of processivity in multi-step oxidations, and the roleof the accessory protein cytochrome b 5.
Catalytic Mechanism of Aromatic Nitration by Cytochrome P450 TxtE: Involvement of a Ferric-Peroxynitrite Intermediate
Findings provide the first detailed insight into the mechanism of nitration by a member of the TxtE subfamily and highlight how the enzyme facilitates this novel reaction chemistry.
Metabolism of halogenated alkanes by cytochrome P450 enzymes. Aerobic oxidation versus anaerobic reduction.
This work investigates the oxidative and reductive P450-mediated activation of tetra- and trichloromethane as halogenated models with density functional theory (DFT) methods and finds a novel mechanism that is different from the well accepted P450 substrate activation mechanisms reported previously.
Glimpsing the Critical Intermediate in Cytochrome P450 Oxidations
The key intermediate in the oxidation of carbon-hydrogen bonds by cytochrome P450 has been characterized and used Mössbauer and electron paramagnetic resonance spectroscopy, in concert with optical absorption spectroscopic, to characterize this hot oxidant in P450 catalysis as an Fe(IV)-oxo-porphyrin cation radical.
Overview: Some Basic Controversies and Applications of Cytochrome P450 Compound I
  • Zhi-Wen Xi
  • Chemistry, Biology
    2021 5th International Conference on Computational Biology and Bioinformatics
  • 2021
The oxygen rebound mechanism proposed by Groves in the catalytic cycle was proved to be a radical process by kinetics characterization and was verified to be the main reactant to conduct hydrogen abstraction through comparative reactivity experiments.
Spectroscopic studies of the cytochrome P450 reaction mechanisms.
  • P. Mak, I. Denisov
  • Chemistry
    Biochimica et biophysica acta. Proteins and proteomics
  • 2018
Structure and function of the cytochrome P450 peroxygenase enzymes
The biochemical properties of the P450 peroxygenases are focused on and on their biotechnological applications with respect to production of volatile alkenes as biofuels, as well as other fine chemicals.
Spectroscopic features of cytochrome P450 reaction intermediates.


Kinetic Characterization of Compound I Formation in the Thermostable Cytochrome P450 CYP119*
The kinetics of formation and breakdown of the putative active oxygenating intermediate in cytochrome P450, a ferryl-oxo-(π) porphyrin cation radical (Compound I), have been analyzed in the reaction
Quantitative production of compound I from a cytochrome P450 enzyme at low temperatures. Kinetics, activation parameters, and kinetic isotope effects for oxidation of benzyl alcohol.
Comparison of values extrapolated to 22 degrees C of both the rate constant for oxidation of C(6)H(5)CD(2)OH and the KIE for the nondeuterated and dideuterated substrates to values obtained previously in laser flash photolysis experiments suggested that tunneling could be a significant component of the total rate constant at -50 degrees C.
The catalytic pathway of cytochrome p450cam at atomic resolution.
Structures were obtained for three intermediates in the hydroxylation reaction of camphor by P450cam with trapping techniques and cryocrystallography and reveal a network of bound water molecules that may provide the protons needed for the reaction.
Cryotrapped Reaction Intermediates of Cytochrome P450 Studied by Radiolytic Reduction with Phosphorus-32*
The UV-visible optical spectra of the reduced oxygenated state of CYP101 are determined and it is shown that the primary intermediate, a hydroperoxo-P450, is stable below 180 K and converts smoothly to the product complex at ∼195 K and no spectral changes indicating the presence of oxoferryl species was observed.
Hydrocarbon hydroxylation by cytochrome P450 enzymes.
Although these proteins have properties that make them particularly attractive for engineering purposes, the large reservoir of P450 enzymes that collectively catalyze an astounding diversity of reactions suggests that P450 catalysis will develop into a highly useful technology.