PROKARYOTIC NAT GENES
Human NAT alleles/haplotypes
Non-human NAT alleles/haplotypes
The Database of Arylamine N-Acetyltransferases (NATs)
The NAT website
(NATs, EC 18.104.22.168) are polymorphic enzymes
responsible for the inter-individual variability in the effect of arylamine
drugs and carcinogens in human populations. Humans have two NAT isoenzymes,
encoded by polymorphic genes (NAT1 and NAT2)
on chromosome 8p22. A third inactive locus, the pseudogene NATP1, is located between NAT1 and
NAT2 in humans. Loci homologous to the human NAT genes have
been identified in several eukaryotic species (including protists,
fungi and animals), as well as in prokaryotes
The pharmacogenetic and toxicogenetic significance of NAT is
well-established, and there is evidence that the NAT polymorphisms may affect
susceptibility to disease, especially cancer. Today, investigators employ the
NAT family as a model system to study enzymatic structure and function, gene
expression, population genetics, comparative genomics and evolution. NAT
appears to be involved in endogenous cellular functions, possibly mycolic
acid biosynthesis (in prokaryotes)
and folate catabolism (in higher
eukaryotes). It is currently being investigated as a candidate
pharmacological target in tuberculous mycobacteria and as a putative
biomarker in tumors responsive to steroid hormones. More
recently, NATs have also been investigated as enzymes detoxifying xenobiotics
in fungi [References
1-35 for recent reviews on NAT].
of numerous polymorphic NAT alleles in human populations and model
organisms led to the introduction of a consensus nomenclature for NATs in 1995
The NAT Gene Nomenclature Committee was formed at the first
International NAT Workshop that took place in 1998 (Kuranda, Queensland, Australia) .
Nomenclature issues where further discussed during dedicated sessions at the
second (Oxford, UK,
third (Vancouver, Canada,
and fifth (Paris, France, 2010)  NAT Workshops.
committee has published two nomenclature updates [41, 42] to advise
investigators as to the proper use of symbols for the NAT genes and
General instructions regarding the
correct naming of genes are available from the HUGO Gene
Nomenclature Committee, which has approved NAT as
the official gene symbol for arylamine N-acetyltransferase. The basic rules for
naming NAT genes and alleles are described in [36, 41 and 42]
and outlined below:
genes and alleles in all species except rodents are all uppercase (NAT).
In rodents, only the first letter is uppercase, followed by lowercase (Nat).
Protein products are always all uppercase (NAT, for rodent species too).
alleles are always italicized (NAT or Nat), while protein
products are not (NAT for rodent and other species).
nomenclature is species-specific. An official organism identification code
should precede the gene symbol [e.g. (MOUSE)Nat]. This code is
available from NEWT.
For the purpose of taxonomic classification, a unique identification number
(available from the same database) should be provided for each species (e.g. 10090 for Mus musculus), but not
incorporated in the gene or allele symbol.
numerals placed immediately after the NAT symbol indicate different NAT
genes of the same organism [e.g. (RABIT)NAT1 and (RABIT)NAT2 are
two distinct genes of the rabbit, encoding for two functionally differentiated
numerals separated from the gene symbol with an asterisk indicate different
alleles of the same NAT gene [e.g. (MACMU)NAT2*1 and (MACMU)NAT2*2
are two polymorphic alleles of the NAT2 gene of the Rhesus macaque
and they produce variants of the NAT2 isoenzyme]. The asterisk is replaced by
space or underscore in the non-italicized symbol of the corresponding
allozymes [i.e. (MACMU)NAT2_1 and
(MACMU)NAT2_2 are the protein variants produced by
the polymorphic (MACMU)NAT2*1 and (MACMU)NAT2*2 alleles of the
Rhesus NAT2 gene].
than one NAT loci are discovered in a specific genome, the symbols NAT1,
NAT2 etc. should be assigned hierarchically, according to the deduced
amino acid identity between each new sequence and a NAT reference sequence.
The reference sequences are: the NAT1
protein of Salmonella typhimurium LT2 (accession no. BAA14331) for bacteria, the deduced NAT1 protein of Halogeometricum borinquense, strain
DSM 11551 (accession no. BN001449) for archaea, the NAT1 protein of Gibberella
moniliformis (accession no. EU552489) for fungi and the NAT1
protein of Homo sapiens (accession no. X17059) for animals. In the case of
protists, which constitute a highly divergent domain of eukaryotic life,
investigators are encouraged to contact the NAT committee for advice on
appropriate reference sequences . For example, a gene
of the Rhesus macaque that encodes a protein with 94% identity to human NAT1
is assigned symbol NAT1 and a second gene, whose product is only 82%
identical to human NAT1, is assigned symbol NAT2. If functional data is available, these should be taken
into account when allocating symbols to new NAT genes, especially if
the identity to the reference sequence is not sufficiently informative. For
example, rabbit NAT1 and NAT2 are both 75% identical to human NAT1, but
studies have demonstrated that rabbit NAT1 and human NAT1 (as well as rabbit
NAT2 and human NAT2) are functionally equivallent. The only exception to this rule is the rodents, where the Nat2 gene is
functionally more similar to human NAT1 and vice versa. Although
confusing, the NAT nomenclature of rodents is widely accepted by scientists
in the field and is currently a consensus.
In humans, the
reference alleles/haplotypes of the NAT1
and NAT2 genes are designated
symbols NAT1*4 and NAT2*4. Human haplotypes are
commonly grouped into specific allelic groups, based on shared signature SNPs
(e.g. all haplotypes belonging to the NAT2*5
allelic group share signature SNP 341T>C
and are classified as NAT2*5A, *5B, *5C
etc.). For human SNPs, it is useful to also
indicate the official “rs” numbers
identifying the polymorphism in the dbSNP database
(e.g. SNP 341T>C is identified
species, the reference allele of a NAT gene is assigned symbol NAT1*1.
This is usually either the wild type allele or the first allele identified
for a specific organism. The capital letters used to indicate NAT allelic
groups in the humans (e.g. NAT2*5A, *5B, *5C etc.) should not be used
in non-human NAT symbols, even if two alleles share common SNPs (e.g.
former rat alleles Nat2*21A and Nat2*21B have now been
discontinued and replaced with Nat2*2 and Nat2*3).
not reported for the NAT genes of non-human species, unless they are
validated experimentally. Likewise, SNPs identified outside the open reading
frame of human or non-human NAT genes (e.g. in the promoter,
5΄-/3΄-untranslated regions or introns) are not reported, unless a
functional effect is demonstrated.
To add a
non-human NAT gene to the database, the sequence of the open reading
frame and deduced protein product should be provided, together with the
official (latin) name of the species. Additional information, e.g. regarding
the position of SNPs or non-coding exons, may also accompany the submission. If available, previous
scientific literature relevant to the submitted sequences should be provided.
reporting the position of SNPs, non-coding exons, transcriptional regulatory
elements etc. of NAT genes, the A of the ATG translation initiation
codon should always be considered as number 1. Upstream positions are
designated with negative numbers and downstream positions with positive
who wish to name new NAT sequences should follow the above rules and
contact the NAT Gene Nomenclature Committee who will approve the official
symbols of the new NAT genes or alleles. The NAT committee encourages
colleagues to request official symbols for NAT sequences prior to
their publication in the scientific literature, as well as to submit their
gene-specific data to the NAT website (see below), whenever they judge that this
information can be made public. Release of gene-specific data on the NAT
website does not preclude its submission to central sequence repositories,
such as the EMBL/GenBank/DDBJ databases, which is encouraged.
The NAT website
website, launched and maintained by Dr. D. Hein at the University of Louisville,
was created by the NAT Gene Nomenclature Committee after the 1998 NAT
workshop and contained information relevant to the consensus nomenclature of
all NAT genes and alleles in humans and other organisms [37, 41].
At the 2007 NAT workshop, it was agreed that a second website, launched and maintained by Dr. S.
Boukouvala at the University
of Thrace [39, 42, 44],
would be dedicated to the nomenclature of non-human NAT genes. With
the number of NAT-homologous genes identified in sequenced prokaryotic
and eukaryotic genomes increasing day after day, these databases were
intended as a useful
resource for investigators who wish to study the genetic, evolutionary and
functional diversity of the NAT isoenzymes. At the 2010 NAT workshop, it was
decided that the two websites would be consolidated into a single website
hosted by the University
of Thrace and providing
annotated information about both human and non-human NAT genes and alleles. As of 2013, all requests for new NAT gene or allelic symbols should be directed to Dr. S.
who will review each submission with other committee members and will
official symbols according to the above guidelines.
- Boukouvala, S. and Fakis, G.
(2005) Arylamine N-acetyltransferases: what we
learn from genes and genomes. Drug Metab. Rev. 37(3),
- Butcher, N.J.; Boukouvala, S.; Sim, E. and Minchin, R.F. (2002) Pharmacogenetics
of the arylamine N-acetyltransferases.
Pharmacogenomics J. 2(1), 30-42.
- Butcher, N.J. and Minchin, R.F. (2012) Arylamine
N-acetyltransferase 1: a novel drug target in cancer development.
Pharmacol. Rev. 64(1), 147-165.
- Butcher, N.J.; Tiang, J. and Minchin, R.F. (2008)
of arylamine N-acetyltransferases. Curr. Drug Metab. 9(6),
- Cascorbi, I. (2006) Genetic
basis of toxic reactions to drugs and chemicals. Toxicol. Lett. 162(1),
- Dupret, J.M. and Rodrigues-Lima, F. (2005)
and regulation of the drug-metabolizing enzymes arylamine N-acetyltransferases. Curr.
Med. Chem. 12(3), 311-318.
- Erickson, R.P. (2010) Genes,
environment, and orofacial clefting: N-acetyltransferase and folic acid.
J. Craniofac. Surg. 21(5), 1384-1387.
- García-Martín, E. (2008) Interethnic
and intraethnic variability of NAT2 single nucleotide polymorphisms Curr.
Drug Metab. 9(6), 487-497.
- Golka, K.; Prior, V.; Blaszkewicz, M. and Bolt, H.M.
(2002) The enhanced bladder cancer
susceptibility of NAT2 slow acetylators towards aromatic amines: a
review considering ethnic differences. Toxicol. Lett. 128(1-3),
- Grant, D.M. (2008) Structures
of human arylamine N-acetyltransferases Curr. Drug Metab. 9(6),
- Grant, D.M.; Goodfellow, G.H.; Sugamori, K. and
Durette, K. (2000) Pharmacogenetics of the human
arylamine N-acetyltransferases Pharmacology 61(3),
- Hein, D.W. (2002) Molecular
genetics and function of NAT1 and NAT2: role in aromatic amine
metabolism and carcinogenesis. Mutat. Res. 506-507, 65-77.
- Hein, D.W. (2006) N-acetyltransferase
2 genetic polymorphism: effects of carcinogen and haplotype on urinary
bladder cancer risk. Oncogene 25(11), 1649-1658.
- Hein, D.W. (2009) N-acetyltransferase
SNPs: emerging concepts serve as a paradigm for understanding
complexities of personalized medicine. Expert Opin. Drug Metab. Toxicol. 5(4), 353-366.
- Hein, D.W.; Doll, M.A.; Fretland, A.J.; Leff, M.A.;
Webb, S.J.; Xiao, G.H.; Devanaboyina, U.S.; Nangju, N.A. and Feng, Y.
(2000) Molecular genetics and epidemiology of
the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol. Biomarkers Prev. 9(1), 29-42.
- Meisel, P. (2002) Arylamine N-acetyltransferases and drug
response. Pharmacogenomics 3(3), 349-366.
- Minchin, R.F.; Hanna, P.E.; Dupret, J.M.; Wagner,
C.R.; Rodrigues-Lima, F. and Butcher, N.J. (2007) Arylamine
N-acetyltransferase I. Int.
J. Biochem. Cell Biol. 39(11), 1999-2005.
- Pompeo, F.; Brooke, E.; Kawamura, A.; Mushtaq, A. and
Sim, E. (2002) The pharmacogenetics of NAT: structural
aspects. Pharmacogenomics 3(1), 19-30.
- Rodrigues-Lima, F. and Dupret, J.M. (2004) Regulation of
the activity of the human drug metabolizing enzyme arylamine N-acetyltransferase 1: role of
genetic and non genetic factors. Curr. Pharm. Des. 10(20),
- Rodrigues-Lima, F.; Dairou, J. and Dupret, J.M.
(2008) Effect of environmental substances on
the activity of arylamine N-acetyltransferases Curr. Drug
Metab. 9(6), 505-509.
- Rodrigues-Lima, F.;
Dairou, J.; Busi, F. and
Dupret, J.M. (2010) Human
arylamine N-acetyltransferase 1: a drug-metabolizing enzyme and a drug
Drug Targets 11(6), 759-766.
- Rothman, N.; García-Closas, M. and Hein, D.W. (2007)
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. 36(1), 23-28.
- Sim, E.; Fakis, G.; Laurieri, N. and
Boukouvala, S. (2012) Arylamine
N-acetyltransferases--from drug metabolism and pharmacogenetics to
identification of novel targets for pharmacological intervention.
Adv. Pharmacol. 63, 169-205.
- Sim, E.; Lack, N.; Wang, C.J.;
Long, H.; Westwood, I.;
Fullam, E. and Kawamura, A. (2008) Arylamine
N-acetyltransferases: structural and functional implications of
polymorphisms. Toxicology 254(3), 170-183.
- Sim, E.; Payton, M.; Noble, M. and Minchin, R. (2000)
update on genetic, structural and functional studies of arylamine N-acetyltransferases in
eucaryotes and procaryotes. Hum. Mol. Genet. 9(16),
- Sim, E.; Pinter, K.; Mushtaq, A.; Upton, A.; Sandy,
J.; Bhakta, S. and Noble, M. (2003) Arylamine N-acetyltransferases: a
pharmacogenomic approach to drug metabolism and endogenous function. Biochem.
Soc. Trans. 31(3), 615-619.
- Sim, E.; Sandy, J.; Evangelopoulos, D.; Fullam, E.;
Bhakta, S.; Westwood, I.; Krylova, A.; Lack, N. and Noble, M. (2008)
N-acetyltransferases in mycobacteria Curr. Drug Metab. 9(6),
- Sim, E.; Walters, K. and Boukouvala, S. (2008)
From structure to function. Drug Metab. Rev. 40(3),
- Sim, E.; Westwood, I. and Fullam, E. (2007)
Opin. Drug Metab. Toxicol. 3(2), 169-184.
- Stanley, L.A. and Sim, E. (2008) Update
on the pharmacogenetics of NATs: structural considerations. Pharmacogenomics
- Upton, A.; Johnson, N.; Sandy, J. and Sim, E. (2001)
N-acetyltransferases - of
mice, men and microorganisms. Trends
Pharmacol. Sci. 22(3), 140-146.
- Walraven, J.M.; Trent, J.O. and Hein, D.W. (2008)
analyses of single nucleotide polymorphisms in human N-acetyltransferase 1. Drug
Metab. Rev. 40(1), 169-184.
- Walraven, J.M.; Zang, Y.; Trent, J.O. and Hein, D.W.
(2008) Structure/function evaluations of
single nucleotide polymorphisms in human N-acetyltransferase 2. Curr.
Drug Metab. 9(6), 471-486.
- Weinshilboum, R. and Wang, L. (2004) Pharmacogenomics:
bench to bedside. Nat. Rev. Drug Discov. 3(9), 739-748.
- Westwood, I.M.; Kawamura, A.; Fullam, E.; Russel,
A.J.; Davies, S.G. and Sim, E. (2006) Structure
and mechanism of arylamine N-acetyltransferases.
Curr. Top. Med. Chem. 6(15), 1641-1654.
- Vatsis, K.P.; Weber, W.W.; Bell, D.A.; Dupret, J.M.;
Price-Evans, D.A.; Grant, D.M.; Hein, D.W.; Lin, H.J.; Meyer, U.A.;
Relling, M.V.; Sim, E.; Suzuki, T. and Yamazoe, Y. (1995) Nomenclature
for N-acetyltransferases. Pharmacogenetics 5(1), 1-17.
- Ilett, K.F.; Kadlubar, F.F. and Minchin, R.F. (1999)
International Meeting on the Arylamine N-Acetyltransferases: synopsis of the workshop on
nomenclature, biochemistry, molecular biology, interspecies comparisons,
and role in human disease risk. Drug Metab. Dispos. 27(9),
- Rodrigues-Lima, F.; Blömeke, B.; Sim, E. and Dupret,
J.M. (2002) NAT – from bugs to brains. An overview
of the 2nd International Workshop on the arylamine N-acetyltransferases. Pharmacogenomics J. 2(3),
- Boukouvala, S.; Westwood, I.M.; Butcher, N.J. and
Fakis, G. (2008) Current trends
research arising from the 2007 International NAT Workshop. Pharmacogenomics
- Rodrigues-Lima, F.;
Dairou, J.; Laurieri, N.; Busi, F. and
Dupret, J.M. (2011) Pharmacogenomics,
biochemistry, toxicology, microbiology and cancer research in one go.
- Hein, D.W.; Grant, D.M. and Sim, E. (2000)
on consensus arylamine N-acetyltransferase
gene nomenclature. Pharmacogenetics 10(4), 291-292.
- Hein, D.W.; Boukouvala, S.; Grant, D.M.; Minchin,
R.F. and Sim, E. (2008) Changes
in consensus arylamine N-acetyltransferase
gene nomenclature. Pharmacogenet. Genomics 18(4), 367-368.
- Glenn, A.E.; Karagianni, E.P.; Ulndreaj, A. and
Boukouvala, S. (2010) Comparative
genomic and phylogenetic investigation of the xenobiotic metabolizing
arylamine N-acetyltransferase enzyme family. FEBS Lett. 584(14), 3158-3164.
- Vagena, E.; Fakis, G. and Boukouvala, S. (2008) Arylamine
N-acetyltransferases in prokaryotic and eukaryotic genomes: A
survey of public databases. Curr. Drug Metab. 9(7), 628-660.
NAT Gene Nomenclature Committee:
Department of Molecular
Biology & Genetics,
Democritus University of Thrace,
Prof. David W. Hein
Pharmacology & Toxicology,
of Louisville, USA.
Prof. Denis M.
Pharmacology & Toxicology,
of Toronto, Canada.
Prof. Edith Sim
of Oxford, UK.
of Science, Engineering & Computing,
Kingston University London, UK.
Prof. Rodney F.
School of Biomedical
of Queensland, Australia.
Prof. José A.G
of Extremadura, Spain.
Dr. Fernando Rodrigues-Lima
CNRS, EAC4413 Laboratory
of Molecular and Cellular Responses to Xenobiotics,
University of Paris Diderot,
Created & maintained
Dr. Sotiria Boukouvala
Tel.: +30-25510-30632 firstname.lastname@example.org
Special thanks to:
collection, annotation and presentation of the data
Department of Molecular Biology and Genetics
Democritus University of Thrace, University Campus, Dragana, Building
10, Alexandroupolis, 68100, Greece.