Insights into the O-Acetylation Reaction of Hydroxylated Heterocyclic Amines by Human Arylamine N-Acetyltransferases: A Computational Study

Lau, Edmond Y.; Felton, James S.; Lightstone, Felice C.

doi:10.1021/tx0600999

Cited by 22 publications

(28 citation statements)

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“…Recently, Lau et al investigated the ability of various heterocyclic amine reactive intermediates to fit into the N-acetyltransferase (NAT2) active-site [11]. Using a NAT2 homology model constructed from available crystal structures, docking studies and quantum mechanical calculations of hydroxylated heterocyclic amines revealed that the observed differences in mutagenic activity between NOH-PhIP and NOH-MeIQ are not related to their acetylation reaction with NAT2.…”

Section: Computer Modelingmentioning

confidence: 99%

Mutagenic potency of food-derived heterocyclic amines

Felton

Knize

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The understanding of mutagenic potency has been primarily approached using "quantitative structure activity relationships" (QSAR). Often this method allows the prediction of mutagenic potency of the compound based on its structure. But it does not give the underlying reason why the mutagenic activities differ. We have taken a set of heterocyclic amine structures and used molecular dynamic calculations to dock these molecules into the active site of a computational model of the cytochrome P-450 1A1 enzyme. The calculated binding strength using Boltzman distribution constants was then compared to the QSAR value (HF/6-31G* optimized structures) and the Ames/Salmonella mutagenic potency. Further understanding will only come from knowing the complete set of mutagenic determinants. These include the nitrenium ion half-life, DNA adduct half-life, efficiency of repair of the adduct, and ultimately fixation of the mutation through cellular processes. For two isomers, PhIP and 3-Me-PhIP, we showed that for the 100-fold difference in the mutagenic potency a 5-fold difference can be accounted for by differences in the P450 oxidation. The other factor of 20 is not clearly understood but is downstream from the oxidation step. The application of QSAR (chemical characteristics) to biological principles related to mutagenesis is explored in this report.3

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Section: Computer Modelingmentioning

confidence: 99%

Mutagenic potency of food-derived heterocyclic amines

Felton

Knize

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…For this reason, investigators have used homology modeling techniques to gain clues about the key structural characteristics of mammalian NATs, including the location and potential mechanism(s) of single-nucleotide polymorphism-induced changes and the shape of the active site for computational docking of NAT substrates (Rodrigues-Lima et al, 2001; RodriguesLima and Dupret, 2002;Kawamura et al, 2005;Lau et al, 2006). Quality mammalian NAT structures could be used to rationalize experimental data and screen for potential substrates and inhibitors, potentially pointing to an endogenous physiological role.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies describe what appears to be an inserted sequence in the second domain of mammalian NATs when aligned with bacterial NATs (Payton et al, 2001;Kawamura et al, 2005;Lau et al, 2006). Although this insert is sometimes referred to as a loop or coil because of its unstructured appearance in homology models, the lack of a template structure for this region is immediately responsible for these designations.…”

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confidence: 99%

“…Homology modeling can only generate structure for a target protein sequence if a corresponding template structure sequence is provided. Previously reported studies modeled mammalian NATs with this insert adjacent to the active site pocket (Kawamura et al, 2005;Savulescu et al, 2005;Lau et al, 2006), whereas other studies place it in a different location (Payton et al, 2001) or do not recognize its existence (Rodrigues-Lima et al, 2001).…”

mentioning

confidence: 99%

“…In the latter case, a loop adjacent to the active site pocket could affect the size, shape, and/or accessibility of the active site pocket. In addition, since the location of the loop in a homology model is determined by the placement of the insert in the alignment, as is demonstrated by the differences in previously reported alignments (Payton et al, 2001;Rodrigues-Lima et al, 2001;Savulescu et al, 2005;Lau et al, 2006), it is possible that a slightly different or more optimal alignment could place the insert in a different location.…”

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Computational and Experimental Analyses of Mammalian ArylamineN-Acetyltransferase Structure and Function

Walraven¹,

Trent²,

Hein³

2007

Drug Metab Dispos

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ABSTRACT:Arylamine N-acetyltransferases (NATs) play an important role in the metabolism of arylamine and hydrazine drugs and many arylamine procarcinogens. The two human N-acetyltransferases, NAT1 and NAT2, are widely distributed in human tissues and are highly polymorphic. Although many xenobiotic procarcinogens and drugs are known mammalian NAT substrates, it is unclear what physiological roles these enzymes might play, what endogenous substrates they primarily act upon, or the mechanisms underlying the functional effects of specific NAT gene coding region single-nucleotide polymorphisms. Analyses of mammalian NAT protein structures can greatly help to answer these questions. Homology modeling techniques can be used to approximate mammalian NAT structures using known bacterial NAT crystal structures as templates. In comparison to the bacterial template NATs used for homology modeling, mammalian NATs have a 17-residue insert of unknown structure and function. Homology modeling analyses yielded two different alignments (Modeler 8v1 or 3DCof-fee algorithms) that placed this insert in two likely alternative locations. Secondary structure prediction techniques and experimental analyses of a series of human NAT2 mutants with artificial deletions/replacements of the insert region distinguished one of these alternatives as the most likely insert location and provided a better understanding of its structure and function. This study demonstrates both the utility and limitations of computational structural modeling with proteins that differ as much as the mammalian and bacterial NATs.Arylamine N-acetyltransferases (NATs; EC 2.3.1.5) catalyze the N-acetylation of arylamines and hydrazines and O-acetylation of N-hydroxy-arylamines and heterocyclic amines. These reactions are important for the activation and deactivation of exocyclic aminecontaining procarcinogens, and for the metabolism of some pharmaceutical drugs (Weber and Hein, 1985). In a ping-pong bi-bi reaction mechanism, the enzyme first acetylates the active site cysteine using acetyl-coenzyme A, and then transfers the acetyl group to the substrate's exocyclic nitrogen (N-acetylation) or the oxygen of its oxidized exocyclic nitrogen (O-acetylation) (Hein, 1988). Whereas Nacetylation is typically considered a deactivation step, O-acetylation is an activation step, resulting in the formation of reactive arylnitrenium species that can react with DNA to form adducts (Hanna, 1996). Because human NAT genes are highly polymorphic, it is important to understand how different NAT genotypes alter N-acetylation phenotypes, thereby influencing cancer susceptibilities and pharmaceutical drug toxicities (Hein et al., 2000).Expression of human NAT1 and NAT2 is widely distributed throughout body tissues (Barker et al., 2006;Husain et al., 2007). Although many xenobiotic NAT substrates have been discovered, only one potential endogenous substrate, p-aminobenzoylglutamate, has been discovered (Minchin, 1995). Therefore, it is highly probable that other, yet unknown endogenous NAT s...

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The Biochemistry of Drug Metabolism – An Introduction

Testa

Krämer

2008

Chemistry & Biodiversity

107

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This review continues a general presentation of the metabolism of drugs and other xenobiotics begun in three recent issues of Chemistry & Biodiversity. The present Part is dedicated to reactions of conjugation, namely methylation, sulfonation, and phosphorylation, glucuronidation and other glycosidations, acetylation and other acylations, the formation and fate of coenzyme A conjugates, glutathione conjugation, and the reaction of amines with carbonyl compounds. It presents the many transferases involved, their nomenclature, relevant biochemical properties, catalytic mechanisms, and the reactions they catalyze. Nonenzymatic reactions, mainly of glutathione conjugation, also receive due attention. A number of medicinally, environmentally, and toxicologically relevant examples are presented and discussed.

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Insights into the O-Acetylation Reaction of Hydroxylated Heterocyclic Amines by Human Arylamine N-Acetyltransferases: A Computational Study

Cited by 22 publications

References 63 publications

Mutagenic potency of food-derived heterocyclic amines

Mutagenic potency of food-derived heterocyclic amines

Computational and Experimental Analyses of Mammalian ArylamineN-Acetyltransferase Structure and Function

The Biochemistry of Drug Metabolism – An Introduction

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