Model and Mechanism: N‐Hydroxylation of Primary Aromatic Amines by Cytochrome P450

Ji, Li; Schüürmann, Gerrit

doi:10.1002/anie.201204116

Cited by 70 publications

(91 citation statements)

References 44 publications

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“…This is different from the reaction between methylamine and P450, for which it was concluded that nitrogen oxidation should be more favorable 16b. The mechanism involving preferred hydrogen abstraction is similar to the mechanism proposed for the reaction of aniline 25b…”

Section: Resultsmentioning

confidence: 76%

“…used DFT to investigate the reaction of methylamine that finally gives a nitroso‐type MI and concluded that the nitrogen‐oxidation mechanism is more favorable than the hydrogen‐abstraction mechanism 16b. In the reaction of aniline, however, Ji and Schüürmann showed that hydrogen abstraction is preferred over nitrogen oxidation 25b. In view of these two mechanisms that may be involved in the reactions of primary amines, it is of interest to examine, in addition to the hydrogen‐abstraction mechanism shown in Scheme , the nitrogen‐oxidation mechanism for hydrazine reactions.…”

Section: Introductionmentioning

confidence: 99%

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How Is a Metabolic Intermediate Formed in the Mechanism‐Based Inactivation of Cytochrome P450 by Using 1,1‐Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

Hirao

Chuanprasit

Cheong

et al. 2013

Chemistry A European J

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A precise understanding of the mechanism-based inactivation of cytochrome P450 enzymes (P450s) at the quantum mechanical level should allow more reliable predictions of drug-drug interactions than those currently available. Hydrazines are among the molecules that act as mechanism-based inactivators to terminate the function of P450s, which are essential heme enzymes responsible for drug metabolism in the human body. Despite its importance, the mechanism explaining how a metabolic intermediate (MI) is formed from hydrazine is not fully understood. We used density functional theory (DFT) calculations to compare four possible mechanisms underlying the reaction between 1,1-dimethylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) and the reactive compound I (Cpd I) intermediate of P450. Our DFT calculations provided a clear view on how an aminonitrene-type MI is formed from UDMH. In the most favorable pathway, hydrogen is spontaneously abstracted from the N2 atom of UDMH by Cpd I, followed by a second hydrogen abstraction from the N2 atom by Cpd II. Nitrogen oxidation of nitrogen atoms and hydrogen abstraction from the C-H bond of the methyl group were found to be less favorable than the hydrogen abstraction from the N-H bond. We also found that the reaction of protonated UDMH with Cpd I is rather sluggish. The aminonitrene-type MI binds to the ferric heme more strongly than a water molecule. This is consistent with the notion that the catalytic cycle of P450 is impeded when such an MI is produced through the P450-catalyzed reaction.

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Section: Resultsmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

How Is a Metabolic Intermediate Formed in the Mechanism‐Based Inactivation of Cytochrome P450 by Using 1,1‐Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

Hirao

Chuanprasit

Cheong

et al. 2013

Chemistry A European J

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“…Numerous computational models have been developed to investigate as many as five different potential mechanisms for N- oxidation of aromatic amines. 81–83 While a consensus remains to be reached, computational analyses support two mechanisms: a hydrogen atom transfer (HAT) mechanism (Path A, Scheme 3) and a proton transfer (PT) mechanism (Path B, Scheme 3). …”

Section: N–o Bond Forming Enzymesmentioning

confidence: 99%

“…Computational modeling by Schüürmann et al recently suggested that this pathway is the most feasible route for ArNH 2 hydroxylation. 83 Furthermore, radical-based mechanisms for N–O bond formation have been previously proposed, but not supported with mechanistic studies, for nitroso formation by the di-copper enzyme NspF in ferroverdin biosynthesis (Section 2.5.1) 97 and nitro formation by the di-iron enzyme CmlI in chloramphenicol biosynthesis (Section 2.6.1.1). 98 For NOS, extensive electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) studies have provided evidence that N–O bond formation proceeds through 24 (Section 2.4.1).…”

Section: N–o Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.

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“…Interestingly, a similar pattern has been observed recently for the HAT pathway of the N-hydroxylation of primary aromatic amines, featuring a P450-catalyzed one-step reaction to the rebounded N-hydroxylamine product only in the LS state. 53 By contrast, the respective HS route proceeded through an intermediate that could convert into the rebound product only through a significant and ratedetermining reaction barrier. Note further that regarding the P450-catalyzed α-CH hydroxylation of nitrosamines, which is also subject to a HAT mechanism as well as most alkanes, for both the HS and LS state there have been found intermediates, followed by a reaction barrier only in the HS route (which, however, was lower than the preceding H-abstraction barrier).…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

Computational Biotransformation Profile of Paracetamol Catalyzed by Cytochrome P450

Schüürmann

2015

Chem. Res. Toxicol.

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The P450-catalyzed biotransformation of the analgesic drug paracetamol (PAR) is a long-debated topic, involving different mechanistic hypotheses as well as experimental evidence for the metabolites N-acetyl-p-benzoquinone imine (NAPQI), p-benzoquinone, acetamide, and 3-hydroxy-PAR. During the catalytic cycle of P450, a high-valent iron(IV)-oxo species known as Compound I (Cpd I) is formed as the ultimate oxidant, featuring two energetically close-lying ground states in the doublet (low-spin) and quartet (high-spin) spin states, respectively. In order to clarify the catalytic mechanism, a computational chemistry analysis has been undertaken for both the high- and low-spin routes, employing density functional theory (DFT) including PCM (polarized continuum-solvation model) that yields an approximate simulation of the bulk polarization exerted through the protein. The results demonstrate that hydrogen abstraction transfer (HAT) by the P450 oxidant Cpd I (FeO) is kinetically strongly preferred over the alternative pathways of an oxygen addition reaction (OAR) or two consecutive single-electron transfers (SET). Moreover, only the respective high-spin route yields N-acetyl-p-semiquinone imine (NAPSQI) as an intermediate that is converted to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). By contrast, 3-hydroxy-PAR, acetamide, and p-benzoquinone as electrophilic and redox-active agent are formed predominantly in the low-spin state through reactions that do not involve NAPSQI. Thus, all experimentally observed PAR metabolites are in accord with an initial HAT from the phenolic oxygen, and NAPSQI should indeed be the precursor of NAPQI, both of which are generated only via the high-spin pathway.

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Model and Mechanism: N‐Hydroxylation of Primary Aromatic Amines by Cytochrome P450

Cited by 70 publications

References 44 publications

How Is a Metabolic Intermediate Formed in the Mechanism‐Based Inactivation of Cytochrome P450 by Using 1,1‐Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

How Is a Metabolic Intermediate Formed in the Mechanism‐Based Inactivation of Cytochrome P450 by Using 1,1‐Dimethylhydrazine: Hydrogen Abstraction or Nitrogen Oxidation?

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Computational Biotransformation Profile of Paracetamol Catalyzed by Cytochrome P450

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