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, Hajime; Chuanprasit, Pratanphorn; Cheong, Ying Yi; Wang, Xiaoqing

doi:10.1002/chem.201300689

Cited by 42 publications

(48 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rather, one must use quantum mechanical methods such as DFT. In recent years, several research groups have reported DFT studies of P450 MBI (de Visser et al, 2004; Rydberg and Olsen, 2011; Hirao et al, 2012, 2013a,b; Taxak et al, 2012, 2013a,b). …”

Section: Applications Of Dftmentioning

confidence: 99%

“…Hirao et al also studied the mechanism of metabolic-intermediate formation in the quasi-irreversible MBI of P450 caused by 1,1-dialkylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) (Hirao et al, 2013a). For this MBI, hydrazine is converted to an aminonitrene metabolic intermediate, which in turn binds to the heme iron.…”

Section: Applications Of Dftmentioning

confidence: 99%

“…(B) Energy profiles (kcal/mol) for the four pathways considered. Adapted from Hirao et al (2013a) with permission from the Wiley-VCH.…”

Section: Applications Of Dftmentioning

confidence: 99%

See 2 more Smart Citations

Applications of density functional theory to iron-containing molecules of bioinorganic interest

2014

Self Cite

View full text Add to dashboard Cite

The past decades have seen an explosive growth in the application of density functional theory (DFT) methods to molecular systems that are of interest in a variety of scientific fields. Owing to its balanced accuracy and efficiency, DFT plays particularly useful roles in the theoretical investigation of large molecules. Even for biological molecules such as proteins, DFT finds application in the form of, e.g., hybrid quantum mechanics and molecular mechanics (QM/MM), in which DFT may be used as a QM method to describe a higher prioritized region in the system, while a MM force field may be used to describe remaining atoms. Iron-containing molecules are particularly important targets of DFT calculations. From the viewpoint of chemistry, this is mainly because iron is abundant on earth, iron plays powerful (and often enigmatic) roles in enzyme catalysis, and iron thus has the great potential for biomimetic catalysis of chemically difficult transformations. In this paper, we present a brief overview of several recent applications of DFT to iron-containing non-heme synthetic complexes, heme-type cytochrome P450 enzymes, and non-heme iron enzymes, all of which are of particular interest in the field of bioinorganic chemistry. Emphasis will be placed on our own work.

show abstract

Section: Applications Of Dftmentioning

confidence: 99%

Section: Applications Of Dftmentioning

confidence: 99%

See 1 more Smart Citation

Applications of density functional theory to iron-containing molecules of bioinorganic interest

2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The mechanism of P450 enzymes, with oxidation mechanisms and inhibition has received particular attention [30][31][32][33][34][35][36]. Plant AOS and related atypical P450s in the prostaglandin H 2 to prostacyclin pathway have also been studied extensively.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

Somboon

Ochiai

Treesuwan

et al. 2014

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

“…To describe such reactive processes computationally, one must resort to quantum chemistry. In recent years, quantum chemical studies of P450 MBI using density functional theory (DFT) have become increasingly prevalent [24–29]. …”

Section: Introductionmentioning

confidence: 99%

Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing Drugs

Hirao

Thellamurege

Chuanprasit

et al. 2013

IJMS

Self Cite

View full text Add to dashboard Cite

The metabolism of amine-containing drugs by cytochrome P450 enzymes (P450s) is prone to form a nitrosoalkane metabolic intermediate (MI), which subsequently coordinates to the heme iron of a P450, to produce a metabolic-intermediate complex (MIC). This type of P450 inhibition, referred to as mechanism-based inactivation (MBI), presents a serious concern in drug discovery processes. We applied density functional theory (DFT) to the reaction between N-methylhydroxylamine (NMH) and the compound I reactive species of P450, in an effort to elucidate the mechanism of the putative final step of the MI formation in the alkylamine metabolism. Our DFT calculations show that H-abstraction from the hydroxyl group of NMH is the most favorable pathway via which the nitrosoalkane intermediate is produced spontaneously. H-abstraction from the N–H bond was slightly less favorable. In contrast, N-oxidation and H-abstraction from the C–H bond of the methyl group had much higher energy barriers. Hence, if the conversion of NMH to nitrosoalkane is catalyzed by a P450, the reaction should proceed preferentially via H-abstraction, either from the O–H bond or from the N–H bond. Our theoretical analysis of the interaction between the MI and pentacoordinate heme moieties provided further insights into the coordination bond in the MIC.

show abstract

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

Cited by 42 publications

References 101 publications

Applications of density functional theory to iron-containing molecules of bioinorganic interest

Applications of density functional theory to iron-containing molecules of bioinorganic interest

Mechanistic insights into the catalytic reaction of plant allene oxide synthase (pAOS) via QM and QM/MM calculations

Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing Drugs

Contact Info

Product

Resources

About