Arylamine N -acetyltransferases: Structural and functional implications of polymorphisms

Abstract Arylamine N -acetyltransferases (NATs) catalyse the N -acetylation of arylamines, arylhydroxylamines and arylhydrazines with the acetyl group being transferred from acetylCoenzyme A. As a result of many recent advances in NAT research there have been many recent reviews and the present pape...

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Bibliographic Details
Published in:Toxicology (Amsterdam) 2008-12, Vol.254 (3), p.170-183
Main Authors: Sim, Edith, Lack, Nathan, Wang, Chan-Ju, Long, Hilary, Westwood, Isaac, Fullam, Elizabeth, Kawamura, Akane
Format: Article
Language:English
Subjects:
Animals
Arylamine N-acetyltransferase
Arylamine N-Acetyltransferase - genetics
Arylamine N-Acetyltransferase - metabolism
Bacterial diseases
Biological and medical sciences
Carcinogenesis
Carcinogenesis, carcinogens and anticarcinogens
Chemical agents
Danio rerio
Emergency
Human bacterial diseases
Humans
Infectious diseases
Isoenzymes - genetics
Isoenzymes - metabolism
Medical sciences
Pharmacogenetics
Polymorphism, Genetic
Pseudogenes
Salmonella typhimurium
Substrate Specificity
Toxicology
Tuberculosis
Tuberculosis and atypical mycobacterial infections
Tumors
Zebrafish
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Summary:Abstract Arylamine N -acetyltransferases (NATs) catalyse the N -acetylation of arylamines, arylhydroxylamines and arylhydrazines with the acetyl group being transferred from acetylCoenzyme A. As a result of many recent advances in NAT research there have been many recent reviews and the present paper gives a flavour of the excitement in the field. The NATs, which are cytosolic, were early examples of pharmacogenetic variation. Polymorphism in isoniazid inactivation resulting in slow acetylation was subsequently found to be due to SNPs in the gene encoding the human isoenzyme NAT2. There are two polymorphic genes ( NAT1 and NAT2 ) encoded with a third pseudogene ( NATP ) at human 8p21.3. The gene structure of NAT1 and NAT2 , with a single ( NAT2 ) or multiple ( NAT1 ) distant non-coding exons showing tissue specific splicing, opens possibilities for effects of polymorphisms outside the single coding exon. In humans, the substrate specificities of NAT1 and NAT2 are overlapping but distinct. The NAT2 isoenzyme, predominantly in liver and gut, acetylates sulphamethazine and arylhydrazine compounds. Slow acetylators are at increased risk of toxicity, e.g. isoniazid induced neurotoxicity and hydralazine-induced lupus. The human NAT1 isoenzyme is also polymorphic. It is expressed in many tissues, particularly in oestrogen receptor positive breast cancers. Human NAT1 has an endogenous role in acetylation of a folate catabolite with in vivo evidence from transgenic mice lacking the equivalent gene. For nomenclature see http://louisville.edu/medschool/pharmacology/NAT.html , the website maintained by David Hein. NAT homologues have been identified by bioinformatics analyses in zebrafish and these sequences are described, although the proteins have not yet been characterized. The first NAT crystallographic structure from Salmonella typhimurium identified the mechanism of acetyl transfer via a catalytic triad of Cys, His and Asp residues each essential for activity in all NATs. NATs from mycobacteria aided in identifying the substrate binding site and the acetylCoA binding pocket. Studies on the eukaryotic enzymes by NMR and crystallography have facilitated understanding substrate specificities of human NAT1 (5-aminosalicylate and p-aminobenzoic acid) and human NAT2 (sulphamethazine). The effect of “slow acetylator” SNPs in the coding region predominantly act through creating unstable protein that aggregates intracellularly prior to ubiquitination and degradation.
ISSN:0300-483X
1879-3185
DOI:10.1016/j.tox.2008.08.022