Arylamine N-acetyltransferases: from structure to function.
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.
Sim
Edith
E
Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
Walters
Kylie
K
Boukouvala
Sotiria
S
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D000995:Antitubercular Agents / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism; D001665:Binding Sites; D003600:Cytosol / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007538:Isoniazid / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; D007538:Isoniazid