Arylamine N-acetyltransferases: From Structure to Function

Abstract

Arylamine N-acetyltransferases (NATs) are cytosolic conjugating enzymes which transfer an acetyl group from acetylCoenzyme A to a xenobiotic acceptor substrate. The enzyme has an active site cysteine as part of a catalytic triad with histidine and aspartate. NATs have had an important role in pharmacogenetics. Polymorphism in acetylation (and inactivation) of the anti-tubercular agent isoniazid resides in human NAT2, one of two polymorphic human NATs. In humans there is also a third pseudogene and in rodents there are three isozymes. Comparison of human and rodent NAT enzymes and their genes is aiding our understanding of the roles of the individual isoenzymes. This may have clinical importance since human NAT1 is overexpressed in a sub-population of breast cancers and control of expression of the NAT genes is ripe for investigation. The mammalian NAT enzymes are involved in metabolism of drugs and carcinogens but there is growing evidence, including from transgenic mice, that human NAT1 has an endogenous role in folate degradation. Structural studies and intracellular tracking of polymorphic NAT variants, is contributing to appreciation of how individual mutations result in loss of NAT activity. Genome analyses have identified NAT homologues in bacteria including Mycobacterium tuberculosis, in which the NAT enzyme metabolises inactivation of isoniazid. More intriguingly, deletion of the nat gene in mycobacteria, leads to deficits in cell wall synthesis. Structural comparisons of NATs from prokaryotes and eukaryotes, particularly in relation to CoA binding, provide a platform for understanding how the unique NAT protein fold may lend itself to a wide range of functions.

Key Words :

• N-acetyltransferase
• Pharmacogenetics
• Isoniazid
• Gene expression
• Ubiquitin
• Catalytic triad
• Breast cancer

Acknowledgments

We thank Isaac Westwood, Liz Fullam and Martin Noble for help with figures and Lindsay Johnson for help preparing the manuscript. We are grateful to the Wellcome Trust for continued financial support (ES), the National Scholarship Foundation of Greece (SB) and National Institutes of Health (CA117888 to KJW) and American Cancer Society (RSG-07–186–01-GMC to KJW). We are also pleased to acknowledge colleagues in the NAT research community for enthusiastic exchange of ideas.