Arylamine N-Acetyltransferases – from Drug Metabolism and Pharmacogenetics to Identification of Novel Targets for Pharmacological Intervention

Sim, Edith; Fakis, Giannoulis; Laurieri, Nicola; Boukouvala, Sotiria

doi:10.1016/b978-0-12-398339-8.00005-7

Cited by 51 publications

(56 citation statements)

References 158 publications

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“…NAT2 is a cytosolic protein present predominantly in the digestive tract, although the liver is the principal organ expressing this protein. In addition, the NAT2 principal function is detoxification of xenobiotics and drugs such as INH which is used in anti-TB treatments [40]. On the other hand, immune responses against intracellular pathogen such as M. tuberculosis are responsible for producing defense mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Expression of NAT2 in immune system cells and the relation of NAT2 gene polymorphisms in the anti-tuberculosis therapy in Mexican mestizo population

et al. 2014

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Arylamine N-acetyltransferase 2 (NAT2) metabolizes isoniazid (INH) and Single Nucleotide Polymorphisms (SNP) responsible for its activity has been reported. The aim of this study in the Mexican mestizo population was to evaluate NAT2 expression at the protein level in immune cells, as well as the distribution and frequency of six NAT2 SNPs and their association with anti-TB therapy, by measuring the plasma levels of INH and Acetyl-INH (AcINH). We performed genotyping assays of NAT2 SNPs in 40 TB patients and 121 healthy volunteers by real-time PCR. A method for detecting NAT2 in immune cells using flow cytometry was developed. Plasma concentrations of INH and AcINH were obtained by HPLC in TB patients and the Metabolic Ratio (MR) was calculated. The phenotypes obtained in the healthy volunteers were as follows; 18.87 % of subjects had the rapid acetylator phenotype, 45.45 % had the intermediate phenotype and 39.66 % exhibited the slow acetylator phenotype. In the TB patient group, 35 % of patients had the rapid acetylator phenotype, 32.5 % were intermediate and 32.5 % showed the slow acetylator phenotype. A higher expression level of NAT2 in innate immune cells from TB patients compared to those from healthy volunteers was detected (P < 0.013). In TB patients the MR showed a bimodal distribution with an antimode of 0.7, which was used as a threshold value for acetylator classification. A high correspondence between the rapid and slow acetylator phenotype with MR was demonstrated. In conclusion, the 282C>T, 341T>C, 481C>T, 590G>A, 803A>G, 857G>A SNPs of NAT2 gene provides accurate for prediction of the acetylator phenotype in Mexican mestizo population. A statistical difference was found in frequency of rapid metabolizer phenotype, which was higher in TB patients. In addition, the expression of NAT2 protein in immune cells can lead to further studies related to its functional role in the innate immune response against M. tuberculosis and other xenobiotics metabolized by this enzyme.

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Section: Discussionmentioning

confidence: 99%

Expression of NAT2 in immune system cells and the relation of NAT2 gene polymorphisms in the anti-tuberculosis therapy in Mexican mestizo population

et al. 2014

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“…They have also been shown to play important endogenous roles as well as having potential as novel targets for pharmacological intervention [1], [2].…”

Section: Introductionmentioning

confidence: 99%

“…Both functional genes encode enzymes which catalyse the transfer of an acetyl group from AcCoA to an arylamine resulting in the formation of an amide bond, although their individual substrate specificities differ [2], [3]. One of these enzymes, arylamine N- acetyltransferase Type 2 ((HUMAN)NAT2), is responsible for the acetylation of a range of drugs and xenobiotics and came to prominence because of its role in the polymorphic metabolism of the anti-tubercular agent isoniazid.…”

Section: Introductionmentioning

confidence: 99%

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2

et al. 2014

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Acetyl Coenzyme A-dependent N-, O- and N,O-acetylation of aromatic amines and hydrazines by arylamine N-acetyltransferases is well characterised. Here, we describe experiments demonstrating that human arylamine N-acetyltransferase Type 1 and its murine homologue (Type 2) can also catalyse the direct hydrolysis of acetyl Coenzyme A in the presence of folate. This folate-dependent activity is exclusive to these two isoforms; no acetyl Coenzyme A hydrolysis was found when murine arylamine N-acetyltransferase Type 1 or recombinant bacterial arylamine N-acetyltransferases were incubated with folate. Proton nuclear magnetic resonance spectroscopy allowed chemical modifications occurring during the catalytic reaction to be analysed in real time, revealing that the disappearance of acetyl CH 3 from acetyl Coenzyme A occurred concomitantly with the appearance of a CH 3 peak corresponding to that of free acetate and suggesting that folate is not acetylated during the reaction. We propose that folate is a cofactor for this reaction and suggest it as an endogenous function of this widespread enzyme. Furthermore, in silico docking of folate within the active site of human arylamine N-acetyltransferase Type 1 suggests that folate may bind at the enzyme’s active site, and facilitate acetyl Coenzyme A hydrolysis. The evidence presented in this paper adds to our growing understanding of the endogenous roles of human arylamine N-acetyltransferase Type 1 and its mouse homologue and expands the catalytic repertoire of these enzymes, demonstrating that they are by no means just xenobiotic metabolising enzymes but probably also play an important role in cellular metabolism. These data, together with the characterisation of a naphthoquinone inhibitor of folate-dependent acetyl Coenzyme A hydrolysis by human arylamine N-acetyltransferase Type 1/murine arylamine N-acetyltransferase Type 2, open up a range of future avenues of exploration, both for elucidating the developmental role of these enzymes and for improving chemotherapeutic approaches to pathological conditions including estrogen receptor-positive breast cancer.

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“…2.3.1.5) are phase II xenobiotic-metabolizing enzymes. These xenobioticmetabolizing enzymes play an important role in the biotransformation and biological fates of aromatic amine compounds like drugs, carcinogens, and toxins (1,2). NATs are structurally related to transglutaminases and cysteine proteases and possess a strictly conserved Cys-His-Asp catalytic triad (3)(4)(5).…”

mentioning

confidence: 99%

Structural and Biochemical Characterization of an Active Arylamine N-Acetyltransferase Possessing a Non-canonical Cys-His-Glu Catalytic Triad

Kubiak

Sierra-Gallay

Chaffotte

et al. 2013

Journal of Biological Chemistry

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Background: Catalytic activity of prokaryotic and eukaryotic arylamine N-acetyltransferases (NATs) relies on a strictly conserved catalytic Cys-His-Asp triad. Results: Structural and biochemical studies identified a functional NAT with a Cys-His-Glu catalytic triad. Conclusion:The catalytic triad of these acetyltransferases is more plastic than previously believed. Significance: (BACCR)NAT3 represents the first known functional acetyltransferase with a non-canonical Cys-His-Glu catalytic triad.

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Arylamine N-Acetyltransferases – from Drug Metabolism and Pharmacogenetics to Identification of Novel Targets for Pharmacological Intervention

Cited by 51 publications

References 158 publications

Expression of NAT2 in immune system cells and the relation of NAT2 gene polymorphisms in the anti-tuberculosis therapy in Mexican mestizo population

Expression of NAT2 in immune system cells and the relation of NAT2 gene polymorphisms in the anti-tuberculosis therapy in Mexican mestizo population

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2

Structural and Biochemical Characterization of an Active Arylamine N-Acetyltransferase Possessing a Non-canonical Cys-His-Glu Catalytic Triad

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