human N-acetyltransferase 1 (arylamine N-acetyltransferase) with S-(2-anilino-2-oxoethyl)-L-cysteine

Arylamine N-acetyltransferases (NATs; EC 2.3.1.5) catalyze the Acetyl CoA-dependent N-acetylation of primary aromatic amines and hydrazines, as well as the O-acetylation of their N-hydroxylated metabolites, thereby influencing the biological activity and toxicity of this class of chemicals. NAT enzyme activity therefore plays an important role in determining the duration of action and pharmacokinetics of aromatic amine containing drugs used in clinical therapy, as well as in influencing the balance between detoxification and metabolic activation of aromatic amine procarcinogens. In the latter regard, N-acetylation reactions are considered to be protective, since the resulting arylacetamide derivatives are chemically stable, while O-acetylation produces acetoxy esters that can spontaneously decompose to electrophilic, DNA-binding nitrenium ions. Thus a better understanding of the structural features of NATs that contribute to their relative abilities to catalyze such reactions for various amine substrates may be of considerable predictive value in optimizing drug development and biomedical toxicology.

Two NATs, NAT1 and NAT2, have been annotated in the human genome. Each of these enzymes is genetically variable in human populations, with variable activity of NAT2 being responsible for the classical acetylation polymorphism that was discovered over half a century ago with the advent of isoniazid therapy for tuberculosis. In addition to isoniazid, the disposition of several other therapeutically useful drugs is affected by defective NAT2 function, including hydralazine, phenelzine, procainamide and some of the sulfonamide antibacterials. NAT1 is highly homologous to NAT2 yet kinetically distinct, such that certain aromatic amines (such as isoniazid and sulfamethazine) are preferentially acetylated by NAT2 while others (such as p-aminosalicylic acid and p-aminobenzoic acid) are selective substrates for NAT1. NAT1 is also genetically variable in human populations. Numerous epidemiological studies have reported associations between both NAT1 and NAT2 variation and the occurrence of cancers related to exposure to aromatic amines (such as 4-aminobiphenyl and 2-naphthylamine) in the environment, although in many instances such findings have been contradictory.

NAT enzyme orthologues are also present in most (but not all) mammalian species, as well as in prokaryotes. Although the crystal structures of some prokaryotic NAT enzymes have been reported, eukaryotic NATs have so far eluded any attempts at the solution of a crystal structure. Here we present the high-resolution X-ray structure of human NAT1.