Arylamine N‐Acetyltransferases

Abstract

Arylamine N -acetyltransferases (NATs) are cytosolic conjugating enzymes that add an acetyl group from acetyl coenzyme A (CoA) to arylamine and arylhydrazines that in general are detoxification reactions. Acetylation of arylhydroxylamines and the transfer of an acetyl group from the O to N group of arylacetohydroxates generally result in activation particularly of arylamine carcinogens to produce N -acetoxyesters. The polymorphic NAT enzymes were very important in establishing the basics of pharmacogenetics through the metabolism of the antitubercular hydrazine isoniazid. There are now known to be two human isoenzymes: NAT2 responsible for isoniazid metabolism and NAT1, also polymorphic, which is more specific for p -aminosalicylate (pAS) and p -aminobenzoic acid ( p -aba) and the folate catabolite, p -aminobenzoylglutamate ( p -abaglu). The polymorphism in NAT1 and NAT2 is primarily through a series of SNPs that occur in haplotypes in the single-exon coding region of these genes. Amino acid substitutions result in destabilized protein with mutant versions being degraded in the proteasome following ubiquitination. There are NAT enzymes in mammalian (apart from canids), nonmammalian, and also bacterial species. Transgenic mice are helping to unravel the endogenous role of human NAT1 that is widespread in tissues, expressed very early in development and overexpressed in estrogen-receptor-positive breast cancer. It is likely that the NAT1 enzyme has a role in maintaining folate and acetyl CoA homeostasis through its role as a folate-dependent acetyl CoA hydrolase.