Formation of the Active Species of Cytochrome P450 by Using Iodosylbenzene: A Case for Spin‐Selective Reactivity

Cho, Kyung‐Bin; Moreau, Yohann; Kumar, Devesh; Rock, Dan A.; Jones, Jeffrey P.; Shaik, Sason

doi:10.1002/chem.200601704

Cited by 47 publications
(69 citation statements)

~~References 59 publications~~

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“…Theoretical methods provide useful tools for estimating enzyme-substrate interaction, and have been a particularly useful tool in understanding P450 enzymes [14–16]. In order to see if theoretical methods could be used to estimate the energetics of type II binding relative to water coordinated ferric iron, we conduct DFT computational calculations on pyridine coordinated to the heme and water coordinated to the heme.…”

Section: Resultsmentioning
confidence: 99%

See 1 more Smart Citation
The effects of type II binding on metabolic stability and binding affinity in cytochrome P450 CYP3A4
Peng
¹
,
Pearson
²
,
Rock
³

et al. 2010
Archives of Biochemistry and Biophysics
27
5
39
0
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One goal in drug design is to decrease clearance due to metabolism. It has been suggested that a compound's metabolic stability can be increased by incorporation of a sp 2 nitrogen into an aromatic ring. Nitrogen incorporation is hypothesized to increase metabolic stability by coordination of nitrogen to the heme iron (termed type II binding). However, questions regarding binding affinity, metabolic stability, and how metabolism of type II binders occurs remain unanswered. Herein, we use pyridinyl quinoline-4-carboxamide analogs to answer these questions. We show that type II binding can have a profound influence on binding affinity for CYP3A4, and the difference in binding affinity can be as high as 1,200 fold. We also find that type II binding compounds can be extensively metabolized, which is not consistent with the dead-end complex kinetic model assumed for type II binders. Two alternate kinetic mechanisms are presented to explain the results. The first involves a rapid equilibrium between the type II bound substrate and a metabolically oriented binding mode. The second involves direct reduction of the nitrogen-coordinated heme followed by oxygen binding.
show abstract

Section: Resultsmentioning
confidence: 99%

“…The basis set, energies of optimized structures and optimized geometries are available as supplemental material. The heme model was the abbreviated heme with an S-H fifth ligand used by Shaik and coworkers [14–16]. …”

Section: Methodsmentioning
confidence: 99%

The effects of type II binding on metabolic stability and binding affinity in cytochrome P450 CYP3A4
Peng
¹
,
Pearson
²
,
Rock
³

et al. 2010
Archives of Biochemistry and Biophysics
27
5
39
0
View full text Add to dashboard Cite

One goal in drug design is to decrease clearance due to metabolism. It has been suggested that a compound's metabolic stability can be increased by incorporation of a sp 2 nitrogen into an aromatic ring. Nitrogen incorporation is hypothesized to increase metabolic stability by coordination of nitrogen to the heme iron (termed type II binding). However, questions regarding binding affinity, metabolic stability, and how metabolism of type II binders occurs remain unanswered. Herein, we use pyridinyl quinoline-4-carboxamide analogs to answer these questions. We show that type II binding can have a profound influence on binding affinity for CYP3A4, and the difference in binding affinity can be as high as 1,200 fold. We also find that type II binding compounds can be extensively metabolized, which is not consistent with the dead-end complex kinetic model assumed for type II binders. Two alternate kinetic mechanisms are presented to explain the results. The first involves a rapid equilibrium between the type II bound substrate and a metabolically oriented binding mode. The second involves direct reduction of the nitrogen-coordinated heme followed by oxygen binding.

~~show abstract~~

“…Only a few studies of the oxidation of tertiary amine nitrogen atoms have been published, all during the latest years. 63,72,77,101 The mechanism is a direct oxygen transfer ( Figure 1) and it occurs in the doublet spin state, which has significantly lower activation energies than the quartet and sextet spin states. The reaction is reversible, as N-oxides of anilines (and possibly also other tertiary amines) can interact with the CYP resting Fe III state and form compound I by transferring the amine oxygen atom back to the heme iron atom.…”

Section: Oxidations Of Aromatic Carbon Atomsmentioning
confidence: 99%

“…four oxidations of nitrogen atoms in six-membered rings and three oxidations of nitrogen atoms in five-membered rings ( Figure 14). 64 The calculations were performed for the doublet spin state, assuming that this is the lowest-lying spin state, as have been found for other types of nitrogen oxidations, 63,77,101 with the aromatic ring in a side-on geometry (as described in Figure 10). The activation energies are quite high compared to other reaction mechanisms, varying between 71 and 102 kJ/mol (see Figure 4).…”

Section: Oxidations Of Tertiary Amine Nitrogen Atomsmentioning
confidence: 99%

Quantum-Mechanical Studies of Reactions Performed by Cytochrome P450 Enzymes
Rydberg
¹
,
Olsen²,
Ryde³
2012
CIC
17
0
6
0
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We review density functional theory studies of various types of reactions performed by the cytochrome P450 family of enzymes. We describe the various reactions on equal footing with an emphasisis on models to predict sites of metabolism for an arbitrary molecule. The activation barriers range between 0 and 109 kJ/mol, depending more on the atoms surrounding the reactive site than on the type of reaction. Therefore, the intrinsic reactivity can rather well be predicted by simple chemical rules. However, for a full predictive model, the steric effects of the enzyme surrounding the heme group need also to be modeled, which often is harder.

~~show abstract~~

“…The B3LYP functional was used with the LANL2DZ basis set with effective core potential on iron and the 3-21G basis set on all other elements. The heme model was the abbreviated heme with an S-H fifth ligand that has been used by Shaik and coworkers [22,23]. The nitrogen atom was positioned over the heme and optimized using the DIIS algorithm.…”

Section: 0 Theory/calculationmentioning
confidence: 99%

The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1
Jones
¹
,
Joswig-Jones
²
,
Hebner
³

et al. 2011
Chemico-Biological Interactions
20
0
22
0
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A descriptor based computational model was developed for cytochrome P450 2E1 (CYP2E1) based on inhibition constants determined for inhibition of chlorzoxazone, or 4-nitrophenol, metabolism. An empirical descriptor for type II binding was developed and tested for a series of CYP2E1 inhibitors. Inhibition constants where measured for 51 different compounds. A fast 2-dimensional predictive model was developed based on 40 compounds, and tested on 8 compounds of diverse structure. The trained model (n= 40) had 2 an r value of 0.76 and an RMSE of 0.48. The correlation between the predicted and actual pKi values of the test set of compounds not included in the model gives an r2 value of 0.78. The features that described binding include heme coordination (type II binding), molecular volume, octanol/water partition coefficient, solvent accessible surface area, and the sum of the atomic polarizabilities. The heme coordination parameter assigns an integer between 0 and 6 depending on structure, and is a new descriptor, based on simple quantum chemical calculations with correction for steric effects. The type II binding parameter was found to be important in obtaining a good correlation between predicted and experimental inhibition constants increasing the r2 value from 0.38 to 0.77.

~~show abstract~~

Formation of the Active Species of Cytochrome P450 by Using Iodosylbenzene: A Case for Spin‐Selective Reactivity

Cited by 47 publications

References 59 publications

The effects of type II binding on metabolic stability and binding affinity in cytochrome P450 CYP3A4

The effects of type II binding on metabolic stability and binding affinity in cytochrome P450 CYP3A4

Quantum-Mechanical Studies of Reactions Performed by Cytochrome P450 Enzymes

The effects of nitrogen-heme-iron coordination on substrate affinities for cytochrome P450 2E1

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