Genomes and Genes
arylamine n acetyltransferase
Summary: An enzyme that catalyzes the transfer of acetyl groups from ACETYL-COA to arylamines. It can also catalyze acetyl transfer between arylamines without COENZYME A and has a wide specificity for aromatic amines, including SEROTONIN. However, arylamine N-acetyltransferase should not be confused with the enzyme ARYLALKYLAMINE N-ACETYLTRANSFERASE which is also referred to as SEROTONIN ACETYLTRANSFERASE.
- Patin E, Barreiro L, Sabeti P, Austerlitz F, Luca F, Sajantila A, et al. Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes. Am J Hum Genet. 2006;78:423-36 pubmed..On the whole, the patterns observed for NAT2 well illustrate how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present-day susceptibility to disease. ..
- Habalova V, Salagovic J, Kalina I, Stubna J. A pilot study testing the genetic polymorphism of N-acetyltransferase 2 as a risk factor in lung cancer. Neoplasma. 2005;52:364-8 pubmed
- Jiao L, Doll M, Hein D, Bondy M, Hassan M, Hixson J, et al. Haplotype of N-acetyltransferase 1 and 2 and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:2379-86 pubmed..The NAT2*6A/any slow acetylation genotype may be a predisposing factor for pancreatic cancer among diabetics with smoking exposure. Our observations must be confirmed in larger independent studies. ..
- Westwood I, Kawamura A, Fullam E, Russell A, Davies S, Sim E. Structure and mechanism of arylamine N-acetyltransferases. Curr Top Med Chem. 2006;6:1641-54 pubmed..In this review we present an overview of recent structural and activity studies on NAT enzymes, and we outline how in silico methods may be used to predict NAT protein-ligand interactions based on the current knowledge. ..
- Zhang N, Liu L, Liu F, Wagner C, Hanna P, Walters K. NMR-based model reveals the structural determinants of mammalian arylamine N-acetyltransferase substrate specificity. J Mol Biol. 2006;363:188-200 pubmed..Our results represent an important step toward predicting whether arylamines present in new products can be detoxified by mammalian NATs. ..
- Rodrigues Lima F, Dairou J, Diaz C, Rubio M, Sim E, Spaink H, et al. Cloning, functional expression and characterization of Mesorhizobium loti arylamine N-acetyltransferases: rhizobial symbiosis supplies leguminous plants with the xenobiotic N-acetylation pathway. Mol Microbiol. 2006;60:505-12 pubmed..This work also provides the first evidence for acquisition of a xenobiotic detoxification pathway by a plant through symbiosis with a soil microbe. ..
- Holton S, Dairou J, Sandy J, Rodrigues Lima F, Dupret J, Noble M, et al. Structure of Mesorhizobium loti arylamine N-acetyltransferase 1. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005;61:14-6 pubmed..8%. The structure reveals that despite low sequence homology, M. loti NAT1 shares the common fold as reported in previous NAT structures and exhibits the same catalytic triad of residues (Cys-His-Asp) in the active site. ..
- Dupret J, Rodrigues Lima F. Structure and regulation of the drug-metabolizing enzymes arylamine N-acetyltransferases. Curr Med Chem. 2005;12:311-8 pubmed..The recent findings reviewed here provide possible mechanisms by which these non genetic determinants inhibit NAT1 activity and thereby may affect drug efficacy/toxicity. ..
- Wakefield L, Cornish V, Long H, Kawamura A, Zhang X, Hein D, et al. Mouse arylamine N-acetyltransferase 2 (Nat2) expression during embryogenesis: a potential marker for the developing neuroendocrine system. Biomarkers. 2008;13:106-18 pubmed..Altered expression of the human orthologue in breast tumours, in which there is endocrine signalling, suggests that human NAT1 should be considered as a potential biomarker for neuroendocrine tissues and tumours. ..
- Sim E, Westwood I, Fullam E. Arylamine N-acetyltransferases. Expert Opin Drug Metab Toxicol. 2007;3:169-84 pubmed
- Anderton M, Bhakta S, Besra G, Jeavons P, Eltis L, Sim E. Characterization of the putative operon containing arylamine N-acetyltransferase (nat) in Mycobacterium bovis BCG. Mol Microbiol. 2006;59:181-92 pubmed..We propose the enzymes encoded by the putative operon have a similar endogenous role to that of the NAT enzyme and are part of a pathway important for cell wall synthesis. ..
- Wang H, Liu L, Hanna P, Wagner C. Catalytic mechanism of hamster arylamine N-acetyltransferase 2. Biochemistry. 2005;44:11295-306 pubmed..In contrast, an increase in pH-dependent hydrolysis of the acetylated enzyme was not observed over a pH range of 5.2-7.5. On the basis of these observations, a catalytic mechanism for the acetylation of arylamines by NAT2 is proposed. ..
- Madikane V, Bhakta S, Russell A, Campbell W, Claridge T, Elisha B, et al. Inhibition of mycobacterial arylamine N-acetyltransferase contributes to anti-mycobacterial activity of Warburgia salutaris. Bioorg Med Chem. 2007;15:3579-86 pubmed..These studies show that W. salutaris is a useful source of anti-tubercular compounds for further analysis and supports the hypothesis of a link between NAT inhibition and anti-mycobacterial activity. ..
- Murta Nascimento C, Silverman D, Kogevinas M, Garcia Closas M, Rothman N, Tardon A, et al. Risk of bladder cancer associated with family history of cancer: do low-penetrance polymorphisms account for the increase in risk?. Cancer Epidemiol Biomarkers Prev. 2007;16:1595-600 pubmed..Whether these correspond to low-penetrance cancer-predisposing polymorphisms acting together and/or interacting with environmental factors warrants further research. ..
- Boukouvala S, Sim E. Structural analysis of the genes for human arylamine N-acetyltransferases and characterisation of alternative transcripts. Basic Clin Pharmacol Toxicol. 2005;96:343-51 pubmed..Finally, both expressed sequence tag analysis and RT-PCR demonstrated the presence of two differentially utilised polyadenylation signals for NAT1 and NAT2, located about 0.2 and 0.3 kb downstream of the coding region of each gene. ..
- Fuselli S, Gilman R, Chanock S, Bonatto S, de Stefano G, Evans C, et al. Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity. Pharmacogenomics J. 2007;7:144-52 pubmed..NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent. ..
- Barker D, Husain A, Neale J, Martini B, Zhang X, Doll M, et al. Functional properties of an alternative, tissue-specific promoter for human arylamine N-acetyltransferase 1. Pharmacogenet Genomics. 2006;16:515-25 pubmed..These findings imply a fundamental role for P3 in NAT1 regulation and define additional regions for genetic polymorphisms associated with enhanced cancer risk. ..
- Rothman N, Garcia Closas M, Hein D. Commentary: Reflections on G. M. Lower and colleagues' 1979 study associating slow acetylator phenotype with urinary bladder cancer: meta-analysis, historical refinements of the hypothesis, and lessons learned. Int J Epidemiol. 2007;36:23-8 pubmed
- Costa S, Pinto D, Morais A, Vasconcelos A, Oliveira J, Lopes C, et al. Acetylation genotype and the genetic susceptibility to prostate cancer in a southern European population. Prostate. 2005;64:246-52 pubmed..030; OR=0.32, 95% CI 0.12--0.89). Our results indicate a role of NAT2 polymorphisms in the carcinogenic pathway of prostate cancer, specifically in a population of Southern Europe. ..
- Walraven J, Trent J, Hein D. Computational and experimental analyses of mammalian arylamine N-acetyltransferase structure and function. Drug Metab Dispos. 2007;35:1001-7 pubmed..This study demonstrates both the utility and limitations of computational structural modeling with proteins that differ as much as the mammalian and bacterial NATs. ..
- Fullam E, Westwood I, Anderton M, Lowe E, Sim E, Noble M. Divergence of cofactor recognition across evolution: coenzyme A binding in a prokaryotic arylamine N-acetyltransferase. J Mol Biol. 2008;375:178-91 pubmed..It also suggests the cofactor-binding site as a unique subsite to target in drug design directed against NAT in mycobacteria. ..
- Norton J, Witschi M, Luong L, Kawamura A, Ghosh S, Stack M, et al. Synthesis and anticancer activities of 6-amino amonafide derivatives. Anticancer Drugs. 2008;19:23-36 pubmed
- Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, et al. No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2006;15:1043-5 pubmed
- Chan A, Tranah G, Giovannucci E, Willett W, Hunter D, Fuchs C. Prospective study of N-acetyltransferase-2 genotypes, meat intake, smoking and risk of colorectal cancer. Int J Cancer. 2005;115:648-52 pubmed..The influence of NAT2 genotype on this association supports a role for heterocyclic amines in mediating the effect of red meat on colorectal carcinogenesis. ..
- Boukouvala S, Fakis G. Arylamine N-acetyltransferases: what we learn from genes and genomes. Drug Metab Rev. 2005;37:511-64 pubmed..However, these strains will be useful for understanding the involvement of NAT in carcinogenesis, an area extensively investigated by epidemiologists, often with ambiguous results. ..
- Walraven J, Zang Y, Trent J, Hein D. Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2. Curr Drug Metab. 2008;9:471-86 pubmed..This analysis advances understanding of NAT2 structure-function relationships, important for interpreting the role of NAT2 genetic polymorphisms in bioactivation and detoxification of arylamine and hydrazine drugs and carcinogens. ..
- Wakefield L, Cornish V, Long H, Griffiths W, Sim E. Deletion of a xenobiotic metabolizing gene in mice affects folate metabolism. Biochem Biophys Res Commun. 2007;364:556-60 pubmed..These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism. In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described. ..
- Sandy J, Mushtaq A, Holton S, Schartau P, Noble M, Sim E. Investigation of the catalytic triad of arylamine N-acetyltransferases: essential residues required for acetyl transfer to arylamines. Biochem J. 2005;390:115-23 pubmed publisher..We have confirmed that each of the three residues of the triad is essential for acetylation activity...
- Kuo H, Chou S, Hu T, Wu F, Chen D. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and genetic polymorphisms in breast cancer patients. Mutat Res. 2007;631:62-8 pubmed..In conclusion, it was found that oxygen radical generation occurred within carcinoma cells, but the role of polymorphism of specific genes in the development of breast cancer should be evaluated. ..
- Gu J, Liang D, Wang Y, Lu C, Wu X. Effects of N-acetyl transferase 1 and 2 polymorphisms on bladder cancer risk in Caucasians. Mutat Res. 2005;581:97-104 pubmed..02). Our data suggest that having a NAT2 slow acetylator genotype is a significant risk factor for BC, particularly in smokers and older individuals. ..
- Sandy J, Holton S, Fullam E, Sim E, Noble M. Binding of the anti-tubercular drug isoniazid to the arylamine N-acetyltransferase protein from Mycobacterium smegmatis. Protein Sci. 2005;14:775-82 pubmed publisher..The structure of NAT with isoniazid bound will facilitate rational drug design for anti-tubercular therapy...
- Sholto Douglas Vernon C, Sandy J, Victor T, Sim E, Helden P. Mutational and expression analysis of tbnat and its response to isoniazid. J Med Microbiol. 2005;54:1189-97 pubmed..The increased expression in the susceptible isolates suggests that INH affects tbnat expression. tbnat may contribute to INH susceptibility, but in combination with other factors. ..
- Sabbagh A, Darlu P. SNP selection at the NAT2 locus for an accurate prediction of the acetylation phenotype. Genet Med. 2006;8:76-85 pubmed..The results of this study will be helpful for the design of time- and cost-effective pharmacogenetic tests (adapted to specific populations) that could be used as routine tools in clinical practice. ..
- Garcia Martin E. Interethnic and intraethnic variability of NAT2 single nucleotide polymorphisms. Curr Drug Metab. 2008;9:487-97 pubmed
- Belogubova E, Kuligina E, Togo A, Karpova M, Ulibina J, Shutkin V, et al. 'Comparison of extremes' approach provides evidence against the modifying role of NAT2 polymorphism in lung cancer susceptibility. Cancer Lett. 2005;221:177-83 pubmed
- Sørensen M, Autrup H, Tjønneland A, Overvad K, Raaschou Nielsen O. Genetic polymorphisms in CYP1B1, GSTA1, NQO1 and NAT2 and the risk of lung cancer. Cancer Lett. 2005;221:185-90 pubmed..The NAT2 fast acetylator genotype seemed to be protective against lung cancer in light smokers (< or =20 cigarettes/day) and not among heavy smokers (>20 cigarettes/day). ..
- Moslehi R, Chatterjee N, Church T, Chen J, Yeager M, Weissfeld J, et al. Cigarette smoking, N-acetyltransferase genes and the risk of advanced colorectal adenoma. Pharmacogenomics. 2006;7:819-29 pubmed..Our study indicated that NAT2 gene variants associated with a slow acetylator phenotype were more susceptible to the effects of tobacco smoking with respect to adenoma risk, providing leads for disease prevention. ..
- Arnesen T, Van Damme P, Polevoda B, Helsens K, Evjenth R, Colaert N, et al. Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans. Proc Natl Acad Sci U S A. 2009;106:8157-62 pubmed publisher..Thus, although we revealed different N-acetylation patterns in yeast and humans, the major NAT, NatA, acetylates the same substrates in both species. ..
- Sabbagh A, Darlu P. Inferring haplotypes at the NAT2 locus: the computational approach. BMC Genet. 2005;6:30 pubmed
- Possuelo L, Castelan J, de Brito T, Ribeiro A, Cafrune P, Picon P, et al. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. Eur J Clin Pharmacol. 2008;64:673-81 pubmed publisher..05) were independent risk factors for hepatotoxicity. Our findings show that HIV-positive patients that have the slow acetylation profile are significantly associated with a higher risk of developing hepatotoxicity due to anti-TB drugs. ..
- Chiou H, Wu M, Chien W, Cheng Y, Wong R, Chen C, et al. NAT2 fast acetylator genotype is associated with an increased risk of lung cancer among never-smoking women in Taiwan. Cancer Lett. 2005;223:93-101 pubmed..These results suggested never-smoking females with NAT2 fast acetylator were more prone to lung cancer and reflected the possibility that exposure to heterocyclic amines may contribute to the female lung cancer development in Taiwan. ..
- Golka K, Blaszkewicz M, Samimi M, Bolt H, Selinski S. Reconstruction of N-acetyltransferase 2 haplotypes using PHASE. Arch Toxicol. 2008;82:265-70 pubmed..A clear assignment is indispensable in surveys of human bladder cancer caused by aromatic amine exposures. In conclusion, PHASE v2.1.1 software allowed an unambiguous haplotype reconstruction in 2,920 of 2,921 cases (>99.9%). ..
- Wu H, Dombrovsky L, Tempel W, Martin F, Loppnau P, Goodfellow G, et al. Structural basis of substrate-binding specificity of human arylamine N-acetyltransferases. J Biol Chem. 2007;282:30189-97 pubmed..8-, and 1.9-A resolution, respectively. The crystal structures reveal novel structural features unique to human NATs and provide insights into the structural basis of the substrate specificity and genetic polymorphism of these enzymes. ..
- Garcia Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M, Hein D, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005;366:649-59 pubmed..Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence. ..
- Teixeira R, Miranda A, Pacheco A, Lopes M, Fonseca Costa J, Rabahi M, et al. Genetic profile of the arylamine N-acetyltransferase 2 coding gene among individuals from two different regions of Brazil. Mutat Res. 2007;624:31-40 pubmed..This finding has implications in the determination of nationwide policies for use of appropriate anti-TB drugs. ..
- Donald P, Parkin D, Seifart H, Schaaf H, van Helden P, Werely C, et al. The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid. Eur J Clin Pharmacol. 2007;63:633-9 pubmed..Any dose reduction below 6 mg/kg body weight will tend to disadvantage a significant proportion of faster acetylators, but, conversely, SS acetylators require only a 3 mg/kg dose to achieve a satisfactory exposure to INH. ..
- Hein D. N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk. Oncogene. 2006;25:1649-58 pubmed
- Sugamori K, Brenneman D, Grant D. In vivo and in vitro metabolism of arylamine procarcinogens in acetyltransferase-deficient mice. Drug Metab Dispos. 2006;34:1697-702 pubmed..The elucidation of the role that N-acetylation plays in the clearance of procarcinogenic agents is the first step in attempting to correlate metabolism by NATs to toxic outcome prevention or augmentation. ..
- Chaudhary S, Behari M, Dihana M, Swaminath P, Govindappa S, Jayaram S, et al. Association of N-acetyl transferase 2 gene polymorphism and slow acetylator phenotype with young onset and late onset Parkinson's disease among Indians. Pharmacogenet Genomics. 2005;15:731-5 pubmed..32 (1.2-4.48)]. Specific SNPs and SNP haplotypes in NAT2 and slow acetylator phenotype are significantly associated with YOPD and to a lesser extent with LOPD among Indians. ..
- Kawamura A, Westwood I, Wakefield L, Long H, Zhang N, Walters K, et al. Mouse N-acetyltransferase type 2, the homologue of human N-acetyltransferase type 1. Biochem Pharmacol. 2008;75:1550-60 pubmed publisher..We propose that a conformational change in the structure is required in order for ligands to bind to the active site of the protein. ..
- Agundez J, Golka K, Martinez C, Selinski S, Blaszkewicz M, Garcia Martin E. Unraveling ambiguous NAT2 genotyping data. Clin Chem. 2008;54:1390-4 pubmed publisher..This study provides real haplotype data that can be used as a guide to convert NAT2 haplotypes and diplotypes into actual genotypes in white individuals. ..
- Zang Y, Doll M, Zhao S, States J, Hein D. Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2. Carcinogenesis. 2007;28:1665-71 pubmed..Our results suggest that coding region SNPs confer slow acetylator phenotype by multiple mechanisms that also may vary with arylamine exposures. ..
- Jensen L, Hoess K, Mitchell L, Whitehead A. Loss of function polymorphisms in NAT1 protect against spina bifida. Hum Genet. 2006;120:52-7 pubmed
- Patin E, Harmant C, Kidd K, Kidd J, Froment A, Mehdi S, et al. Sub-Saharan African coding sequence variation and haplotype diversity at the NAT2 gene. Hum Mutat. 2006;27:720 pubmed