Human Molecular Genetics, 2000, Vol. 9, No. 16 2435-2441
© 2000 Oxford University Press
An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK, 1The Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK and 2Department of Pharmacology, The University of Western Australia, Nedlands, Western Australia 6907, Australia
Received 19 June 2000; Accepted 5 July 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEUCARYOTIC NATSPROCARYOTIC NATSSTRUCTURE OF NATSCONCLUSIONSREFERENCES |
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Arylamine N-acetyltransferase (NAT) was first identified as the inactivator of the anti-tubercular drug isoniazid. The enzyme was shown to catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of the hydrazine drug. The rate of inactivation of isoniazid was polymorphically distributed in the population and was one of the first examples of pharmacogenetic variation. NAT was identified recently in Mycobacterium tuberculosis and is a candidate for modulating the response to isoniazid. Genome sequences have revealed many homologous members of this unique family of enzymes. The first three-dimensional structure of a member of the NAT family identifies a catalytic triad consisting of aspartate, histidine and cysteine proposed to form the activation mechanism. So far, all procaryotic NATs resemble the human enzyme which acetylates isoniazid (NAT2). Human NAT2 is characteristic of drug-metabolizing enzymes: it is found in liver and intestine. In humans and other mammals, there are up to three different isoenzymes. If only one isoenzyme is present, it is like human NAT1. Human NAT1 and its murine equivalent specifically acetylate the folate catabolite p-aminobenzoylglutamate. NAT1 and its murine homologue each have a ubiquitous tissue distribution and are expressed early in development at the blastocyst stage. During murine embryonic development, NAT is expressed in the developing neural tube. The proposed endogenous role of NAT in folate metabolism, and its multi-allelic nature, indicate that its role in development should be assessed further.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEUCARYOTIC NATSPROCARYOTIC NATSSTRUCTURE OF NATSCONCLUSIONSREFERENCES |
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Genetic variation can contribute to interindividual differences in the pharmacological or toxicological response to a drug (for a review see ref. 1). Pharmacogenetics, as the subdiscipline has become known (2), has grown in importance in the post-genome world because of the possibility of customized therapy for different individuals. Pharmacogenetics has also taken on the mantle of pharmacogenomics, in which individual variations in drug targets can also be envisaged (3). Pharmacogenomics applies not only to the Human Genome Project but also to the genomes of other organisms (4) in which the identification of specific polymorphic targets can arise from the comparison of individual genomes.
Pharmacogenetics and arylamine N-acetyltransferases (or NATs) are inextricably linked, since variation in NAT activity was one of the earliest pharmacogenetic traits to be recognized. NAT was first identified as the genetically controlled step responsible for the inactivation of isoniazid (5), still a front-line anti-tubercular drug (6). NAT research has now come full circle with the recent identification that an NAT homologue, which will inactivate isoniazid by acetylation, is present in Mycobacterium tuberculosis (7,8).
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EUCARYOTIC NATS |
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TOPABSTRACTINTRODUCTIONEUCARYOTIC NATSPROCARYOTIC NATSSTRUCTURE OF NATSCONCLUSIONSREFERENCES |
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NAT enzymes were identified initially as being involved in the metabolism of xenobiotics. Therefore, the understanding of environmentally induced diseases, where substrates of NAT are causative agents, has been a ripe area for approaches to identifying the relationship between environmental and genetic factors. Isoniazid-induced neuropathy (9) and hydralazine-induced systemic lupus erythematosus (10) are examples where toxic side effects to each of these hydrazine drugs is associated with the slow acetylator phenotype. When the disease-causing environmental factor is less easily identified, for example occupational bladder cancer, polymorphism in the acetylation of arylamine carcinogens (also NAT substrates) has been the subject of repeated investigations. The consensus is that slow acetylation type is a contributory risk factor, particularly in Caucasians (11–13). For other cancers, including breast cancer (14,15) and colon cancer (16,17), there is a spread of opinion on the role of acetylation polymorphism. Multi-centre investigations represent one approach to maximizing the cohort size for studies of the role of candidate genes in environmentally induced cancers (18).
The molecular genetics of NAT in humans has revealed the presence of three loci (19), two of which encode distinct but very similar enzymes and the third is a pseudogene. The identification of two discrete and functional loci (20) resolved a long-standing problem in NAT research, namely that some drugs (e.g. procainamide) showed the same interindividual variation as isoniazid (termed polymorphic substrates), whereas others, for example p-aminosalicylate, did not (previously classified as monomorphic substrates) (21). In humans, these two classes of substrate are metabolized by different gene products referred to as NAT1 and NAT2 (19). NAT2 acetylates isoniazid, certain sulfonamides (e.g. sulfamethazine), dapsone (22) and arylamine carcinogens (e.g. aminofluorene) (23). The tissue distribution of NAT2 is that of a typical drug-metabolizing enzyme found in the liver and intestinal epithelium (24–27). If present in other tissues, it is just above the level of detection and RT–PCR is required (28,29).
Human NAT1, in contrast, is found in almost every tissue which has been investigated in addition to liver (20) and gut (27) and including leukocytes and erythrocytes (30,31). NAT1 has a distinct substrate specificity profile and might have an endogenous role in addition to the metabolism of xenobiotics. It acetylates p-aminosalicylate (32) and p-aminobenzoic acid (p-ABA) (33). A potential endogenous substrate has been identified: the folate catabolite p-aminobenzoyl glutamate (p-ABGlu) (34,35) which is excreted in urine as the N-acetyl form (36,37). There is up to a 20-fold difference in acetylation rates of NAT1 substrates amongst different individuals (27,30,31,33, 38–40).
Gene mapping studies in humans have demonstrated that the NAT genes are located between 170 and 360 kb at 8p22 (41,42) adjacent to clusters of CpG islands (43). The coding region of both NAT1 and NAT2 is 870 bp and is intronless (19,20). The region 8p22 is unstable in tumours and frequently is deleted (44–46), with the conclusion that there are tumour suppressor genes in the region (46). Amplification of NAT genes has also been detected in tumours using fluorescence in situ hybridization (FISH) analysis with NAT-specific probes (47).
Both the human NAT1 and the NAT2 loci are highly polymorphic, with >20 alleles known at each locus (48). These alleles result from combinations of point mutations (up to three) at selected bases, and the NAT genes therefore represent a well-characterized series of single nucleotide polymorphisms (SNPs) within an apparently unstable region of the human genome (Fig. 1). This region is likely to provide a useful resource of SNPs for linkage analysis. A well-established polymorphic marker in this region, D8S21, is within the NAT2 locus (43). Although the region is highly polymorphic, there is evidence from haplotype analysis for linkage disequilibrium (49,50): the haplotype NAT1*10, NAT2*4 appears 
3.5 times more frequently than would be expected by chance (49).
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The genotype–phenotype correlation for human NAT2 is well-established (51–53). Two of the known alleles (54) are associated with rapid acetylation, whereas all others are associated with slow acetylation. In Orientals, the fast acetylator phenotype is more frequent (85%) whereas in Caucasians rapid acetylators account for 50% of the population (1). The molecular basis for this discrepancy is that the most common allele at the NAT2 locus in Caucasians is very rare in Orientals (54) and may represent a different selective advantage within the gene pools of these separate populations. New rare alleles of human NAT2 are still being identified (55).
The genotype–phenotype relationship at the NAT1 locus is less clear cut, compared with human NAT2, although a pattern is beginning to emerge (Fig. 1). There are two types of mutation identified in human NAT1 which occur in combination: point mutations, mainly within the coding region, and a series of insertion/deletion mutations at the 3' end of the coding region. Particular point mutations within the coding region are associated with a reduction in activity (32,38–40) and include two rare alleles (NAT1*15 and NAT1*19) which create a premature stop codon (32,16). The haplotype NAT1*15, NAT2*4 has been reported to occur more frequently than expected (56). The other ‘slow’ alleles (NAT1*11 and NAT1*14) are associated with low, yet detectable, levels of activity. The suggestion that the allele NAT1*10 is a ‘rapid’ allele has been a source of much controversy. An initial report, based on a small group of heterozygotes, demonstrated that the NAT1*10 genotypes were associated with a higher range of activities in bladder cytosols (57). However, subsequent studies have failed to detect any such correlation (32,38–40). Genotype alone may not control NAT1 activity since it has been demonstrated in cultured cells that NAT1 expression can be modified by the presence of the NAT1 substrate p-ABA (58). Maintenance of NAT1 activity appears to be important since the majority of NAT1 alleles described are associated with an active gene product.
The suggestion that human NAT1 has an endogenous role is based on its widespread tissue distribution (30–32,59) and that it is expressed early in development (60,61). In human placentas (62), NAT1 is expressed at 1000 times the level of human NAT2 from the earliest stage tested (5 weeks) until term (49,63). Early human embryos have been investigated using cDNA libraries, and NAT1 is first detected at the blastocyst stage (Fig. 2A) (63). The mouse is a useful model to investigate whether the NAT gene products have a role in development. In the mouse, there are three functional NAT genes (64). Following earlier linkage analysis, demonstrating murine NAT on chromosome 8 (65), the murine NAT genes recently have been mapped to 8B3.1–3.3, the homologous region to human 8p22, by FISH analysis with a phage P1-derived artificial chromosome (PAC) clone containing all three murine NAT genes (66).
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Murine NAT2 is the homologue of human NAT1 in terms of substrate specificity and tissue distribution, and is encoded at a polymorphic locus which confers either fast or slow activity. Murine NAT2, like human NAT1, metabolizes p-ABGlu and is expressed in a range of tissues (67–70). During development, the murine NAT2 gene is transcribed in embryonic stem (ES) cells (67). Therefore, as in humans, this isoenzyme with a putative role in folate metabolism is expressed at the blastocyst stage, i.e. prior to neurulation (Fig. 2A). The other murine and human NAT genes are not expressed at this early stage (63,71). The comparison of murine NAT2 and human NAT1 in early development has validated the investigation of the expression of NAT in mice as a model for expression in humans. Using a series of embryos, it has been shown by immunohistochemistry that the murine homologue of human NAT1 is expressed as early as 9.5 days (72). RT–PCR studies on individual tissues from neonatal mice has also demonstrated that there is preferential transcription of the murine NAT2 (73). At 9.5, 11.5 and 13.5 days of gestation, the distribution of murine NAT2 is non-uniform. It is concentrated particularly in the developing neural tube (Fig. 2B) which may be of importance in view of the protective effect of folate in the prevention of neural tube defects (74). In adult mice (72) and other rodents (75), the equivalent of human NAT1 is expressed in the Purkinje cells of the cerebellum (72). Preliminary studies on adult human cerebellum have also demonstrated a similar pattern of NAT1 expression in Purkinje cells (76).
Earlier observations on congenic mice had illustrated that susceptibility to oral clefting co-segregated with NAT type (77) and there is evidence (78) that folate has a protective role in human clefting. The role of NAT in development awaits the results of transgenic and knock-out strains of mice which currently are under development.
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PROCARYOTIC NATS |
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TOPABSTRACTINTRODUCTIONEUCARYOTIC NATSPROCARYOTIC NATSSTRUCTURE OF NATSCONCLUSIONSREFERENCES |
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It was demonstrated initially that human NAT has a role in isoniazid metabolism and inactivation (5). Until recently, Salmonellla typhimurium was the only procaryote where NAT had been identified through association with increased sensitivity of strains of S.typhimurium in mutagenicity testing (79). Within the past 3 years, there have been many other NATs identified in procaryotes (8,80,81). Bacterial NAT substrate specificity is similar to that of human NAT2 in that they are unable to acetylate p-ABA (80,81). This is compatible with the use of p-ABA by procaryotes for de novo folate synthesis.
It is particularly intriguing that NAT has been identified in mycobacteria (8). Mycobacteria, including M.tuberculosis, are exquisitely sensitive to isoniazid. The activation mechanism of isoniazid to the form which inhibits the synthesis of the mycolic acid component of the mycobacterial cell wall is via oxidation (82). Acetylation of isoniazid prevents its oxidation to the active form. Transgenic experiments using M.smegmatis have demonstrated that the level of NAT activity can determine sensitivity to isoniazid (8). These results have implications for isoniazid resistance. There are likely to be many factors contributing to drug resistance in tuberculosis. At present, only 70% of isoniazid resistance can be accounted for by known polymorphisms in genes of the M.tuberculosis genome (83). Mutations in eucaryotic NAT genes can change acetylation activity. It is therefore important to investigate NAT in M.tuberculosis for such polymorphisms, and preliminary investigations suggest that NAT in different clinical M.tuberculosis isolates is also polymorphic (84).
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STRUCTURE OF NATS |
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TOPABSTRACTINTRODUCTIONEUCARYOTIC NATSPROCARYOTIC NATSSTRUCTURE OF NATSCONCLUSIONSREFERENCES |
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NAT may have a variety of roles in different organisms. However, the protein sequences of all NATs belong to the same ‘super-family’. From sequence alignments and site-directed mutagenesis, observations have been made identifying likely key residues, including the active site cysteine (Cys68 in human NAT and Cys69 in S.typhimurium NAT) (8,79,85,86). The structure of the N-terminal 150 residues of the NAT molecule is highly conserved, and a fragment of human NAT1 consisting of the N-terminus alone is sufficient to bind acetyl-CoA (87). Although the C-terminal region is much more variable amongst different members of this family of enzymes, the degree of similarity suggests that determining the structure of one NAT will provide a template to model other members of the NAT family. Recently, the three-dimensional structure of NAT from S.typhimurium has been determined (88) (Fig. 3). An unexpected feature revealed by the structure is that there is an active site catalytic triad which consists of Asp122, His107 and Cys69 (numbered according to the S.typhimurium NAT amino acid sequence). The catalytic triad can be considered to activate the cysteine in a manner analogous to the cysteine proteases of the papain family (89). The residues which make up the active site catalytic triad are highly conserved in all NATs, identified both through functional studies and by comparison with homologues identified in sequenced genomes (8,80). Preliminary analysis of X-ray diffraction data on other NATs, including M.smegmatis, indicates that the corresponding residues are also arranged in a similar catalytic triad. Crystals have been obtained for hamster NAT2 (90), and it is likely that the structure will follow soon. The eucaryotic proteins are much more difficult to handle, being susceptible to proteolysis during the purification stages (35). When all known NAT sequences are aligned, there is a 17 amino acid loop in eucaryotic NATs before the sequence which corresponds to the third, C-terminal, domain of S.typhimurium NAT (8,80). It may be that it is the loop, predicted as a random coil (91), which is susceptible to proteolytic attack.
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It should soon be possible to understand the structural effects of non-conservative point mutations in the eucaryotic and procaryotic NAT genes. The variants in the human enzyme NAT2 which are responsible for the slow acetylation of isoniazid and the murine NAT variant which confers the slow acetylation of substrates, including the proposed endogenous substrate p-ABGlu, have been suggested to be due to less stable enzyme structures (52,55,68). By studying structural information, it should be possible to identify the source of that instability.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONEUCARYOTIC NATSPROCARYOTIC NATSSTRUCTURE OF NATSCONCLUSIONSREFERENCES |
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The combination of epidemiology, molecular genetic, structural and functional studies on NAT has identified many important new avenues for research from tuberculosis to embryonic development. Studies on human NAT have contributed a series of well-defined SNPs. These SNPs, which are within a region showing linkage disequilibrium, will serve as a point of reference for the genetic and physical maps of chromosome 8 and will also aid investigations into multi-factorial diseases.
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ACKNOWLEDGEMENTS |
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We are extremely grateful to the funding agencies (Wellcome Trust, Royal Society, CRC, AICR, MRC and SPARKS) who have funded the research and to the many colleagues and collaborators who have contributed.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 1865 271596; Fax: +44 1865 271853; Email: esim@molbiol.ox.ac.uk
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REFERENCES |
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TOPABSTRACTINTRODUCTIONEUCARYOTIC NATSPROCARYOTIC NATSSTRUCTURE OF NATSCONCLUSIONSREFERENCES |
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