Pharmacogenomics of Arylamine N-acetyltransferase

Adeel      Mushtaq; Matthew      Anderton; Valerie      Cornish

Abstract

The arylamine N-acetyltransferases (NATs) are a unique family of enzymes that catalyse the transfer of an acetyl group from acetyl CoA to the terminal nitrogen of hydrazine and arylamine xenobiotics. They have well characterised roles in drug detoxification and carcinogen activation and NAT homologues are present in numerous species from bacteria to humans. The importance of human NAT in xenobiotic metabolism is well established and much interest has focussed on the significance of the high degree of polymorphism present in the human isozymes. Recent advances, not least of all the availability of genomic information for species as diverse as Mycobacterium smegmatis to Danio Ranio, have seen an expansion in the NAT field. NAT in Mycobacterium tuberculosis has recently been linked to the inactivation of the forefront anti-tubercular agent, isoniazid. The availability of the three-dimensional structures of NAT from Salmonella typhimurium and Mycobacterium smegmatis is aiding investigations into the endogenous role of these and other NAT homologues. There is much speculation as to possible endogenous roles for NAT in both prokaryotes and eukaryotes and the everexpanding depth of genomic information seems likely to provide important clues in this investigation as well as allowing quicker advances in the identification of NAT substrates and inhibitors. Here we review to what extent the availability of genomic information has enabled the identification of NAT homologues in a variety of species and how this is aiding the investigation of the relevance of N-acetylation by NATs both pharmacologically and endogenously.

Keywords: pharmacogenomics, arylamine n-acetyltransferase, arylamine xenobiotics, nat homologues