Arylamine N-acetyltransferases

Abstract

Arylamine N-acetyltransferases (NATs), known as drug- and carcinogen-metabolising enzymes, have had historic roles in cellular metabolism, carcinogenesis and pharmacogenetics, including epidemiological studies of disease susceptibility. NAT research in the past 5 years builds on that history and additionally paves the way for establishing the following new concepts in biology and opportunities in drug discovery: i) NAT polymorphisms can be used as tools in molecular anthropology to study human evolution; ii) tracing NAT protein synthesis and degradation within cells is providing insight into protein folding in cell biology; iii) studies on control of NAT gene expression may help to understand the increase in the human NAT isoenzyme, NAT1, in breast cancer; iv) a NAT homologue in mycobacteria plays an essential role in cell-wall synthesis and mycobacterial survival inside host macrophage, thus identifying a novel biochemical pathway; v) transgenic mice, with genetic modifications of all Nat genes, provide in vivo tools for drug metabolism; and vi) structures of NAT isoenzymes provide essential in silico tools for drug discovery.

Keywords::

• arylamine N-acetyltransferase
• folate
• NAT
• pharmacogenetics
• tuberculosis

Acknowledgements

This article is dedicated to the memory of Joseph Dunbar Strachan 1924 – 2006. We thank the Wellcome Trust for their continued financial support and the MRC for studentships (IW, EF). We are extremely grateful to many students, colleagues and collaborators for helpful discussions and advice, particularly J Sandy, L Wakefield, M Noble and R Gardner. We especially thank A Troen, K Pinter and S Bhakta for help with figures, and D Perera and J Charlton for help in preparing the manuscript.

Notes

The information has been compiled from [32,39,140,142,143]. BCG: Bacillus Calmette–Guérin; NAT: N-acetyltransferase.