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Introduction
Arylamine
N-acetyltransferases (NATs, EC 2.3.1.5) are polymorphic enzymes
responsible for the inter-individual variability in the effect of arylamine and
hydrazine 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 common laboratory animals),
as well as in bacteria. 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 (prokaryotes) and folate catabolism (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. [References 1-28 for recent reviews on NAT].
NAT
nomenclature
The
discovery of numerous polymorphic NAT alleles in human populations and
model organisms led to the introduction of a consensus nomenclature for NATs in
1995 [29].
The NAT Gene Nomenclature Committee was
formed at the first International NAT Workshop that took place in 1998
(Kuranda, Queensland, Australia) [30]. Nomenclature issues where further
discussed during dedicated sessions at the second (Oxford, UK, 2001) [31],
third (Vancouver, Canada, 2004) and fourth (Alexandroupolis, Greece, 2007) [32]
NAT Workshops, and the NAT committee has published two nomenclature updates [33,
34]
to advise investigators as to the proper use of symbols for the NAT genes
and alleles.
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 [29,
33
and 34]
and outlined below:
-
The NAT 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).
- Genes and alleles are always intalicized (NAT
or Nat), while protein products are not (NAT for rodent and other
species).
- The nomenclature is species-specific. An
official organism identification code should precede the gene symbol [e.g.
(MOUSE)Nat]. This code is available from SWISS-PROT/TrEMBL
and NEWT. For the purpose of taxonomic
classification, a unique identification number (available from the same
databases) should be provided for each species (e.g. 10090 for Mus musculus), but not
incorporated in the gene or allele symbol.
- Arabic 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 isoenzymes].
- Arabic 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 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].
- When more 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 prokaryotes and the NAT1 protein of Homo sapiens (accession
no. X17059) for eukaryotes. 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 homologous. The only exception to this rule are
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 non-human 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).
- SNPs are not reported for the NAT genes
of non-human species, unless they are validated experimentally. Likewise, SNPs
identified outside the open reading frame of the NAT genes (e.g. in the
promoter or the 5΄-/3΄-untranslated regions) 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 submission. If available, previous scientific
literature relevant to the submitted sequences should be provided.
- All NAT genes identified to date
have an intronless coding region. When reporting the position of SNPs,
non-coding exons 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
numbers.
Scientists 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 appropriate 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.
The NAT websites
An
official website (“Louisville”) was created by the NAT
Gene Nomenclature Committee after the 1998 NAT workshop, and has since
maintained information relevant to the consensus nomenclature of all NAT genes
and alleles in humans and other organisms [30, 33].
At the 2007 NAT workshop, it was agreed that time had come for the construction
of a second website (“Alexandroupolis”) [32, 34],
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, this new database is anticipated to be a
useful resource for investigators who wish to study the genetic, evolutionary
and functional diversity of the NAT isoenzymes. From now on, the Louisville
website will focus exclusively on the annotation of polymorphisms in the human NAT
genes, reported by individual researchers and international consortia.
Transferred from the Louisville website,
provided in the new database is information about all NAT genes and
alleles described in the literature for non-human species. Additionally, a number
of non-human NAT homologues is presented, that were recovered from major
genomic databases [see references 1 and 35
for annotation of these sequences]. We hope that, in the future, the new
website will expand with contributions of sequences and functional annotations
from many scientists in the NAT field.
The NAT Gene Nomenclature Committee has always
encouraged the input of scientists working with NATs and requests that
investigators consult its members before assigning symbols to newly identified NAT
genes or polymorphic alleles. Data concerning
the human NATs should, from now on, be submitted to the Louisville database,
while those concerning all other organisms (eukaryotic and prokaryotic) should
be directed to the Alexandroupolis database. The contact persons are
Professor David Hein (d.hein@louisville.edu)
in Louisville, and Dr. Sotiria Boukouvala (sboukouv@mbg.duth.gr)
or Dr. Giannoulis Fakis (gfakis@mbg.duth.gr)
in Alexandroupolis. Information reviewed by all members of the NAT nomenclature
committee is incorporated into one of the two databases, following the official
assignment of appropriate gene or allele symbols, according to the above
guidelines.
Literature
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Cascorbi, I. (2006) Genetic basis of
toxic reactions to drugs and chemicals. Toxicol. Lett. 162(1),
16-28.
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García-Martín, E. (2008) Interethnic
and intraethnic variability of NAT2 single nucleotide polymorphisms Curr.
Drug Metab. (6), 487-497.
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Grant, D.M. (2008) Structures of
human arylamine N-acetyltransferases Curr. Drug Metab. 9(6),
465-470.
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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.
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Hein, D.W. (2006) N-acetyltransferase
2 genetic polymorphism: effects of carcinogen and haplotype onurinary
bladder cancer risk. Oncogene 25(11), 1649-1658.
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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.
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Meisel, P. (2002) Arylamine N-acetyltransferases and drug
response. Pharmacogenomics 3(3), 349-366.
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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),
2519-2524.
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Rothman, N.; García-Closas, M. and Hein, D.W. (2007)
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. 36(1),
23-28.
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Sim, E.; Sandy, J.; Evangelopoulos, D.; Fullam, E.;
Bhakta, S.; Westwood, I.; Krylova, A.; Lack, N. and Noble, M. (2008)
Arylamine
N-acetyltransferases in mycobacteria Curr. Drug Metab. 9(6),
510-519.
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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.
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Ilett, K.F.; Kadlubar, F.F. and Minchin, R.F. (1999)
1998
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), 957-959.
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