Nacetyltransferasen

N-acetyltransferases, abbreviated NATs, are enzymes that catalyze the transfer of an acetyl group from acetyl-CoA to a substrate containing a nitrogen atom, commonly forming an N-acetylated product. They play a key role in the metabolism and detoxification of a wide range of xenobiotics, including drugs and aromatic amines. The NAT enzyme family comprises several classes, with the human NAT1 and NAT2 isozymes being the best characterized.

In humans, NAT1 and NAT2 differ in tissue distribution and substrate preference. NAT1 is broadly expressed in many tissues, whereas NAT2 is predominantly expressed in the liver and intestinal mucosa. Genetic polymorphisms in NAT2 give rise to distinct acetylation phenotypes: slow, intermediate, and rapid acetylators. These differences affect the pharmacokinetics of NAT2 substrates such as isoniazid, hydralazine, procainamide, and sulfamazine, influencing efficacy and toxicity. NAT1 polymorphisms also influence metabolism of certain arylamines, though their clinical impact is generally less pronounced than that of NAT2 variants.

Beyond humans, NAT-like enzymes exist in bacteria and other organisms as members of the GNAT (GCN5-related N-acetyltransferase) superfamily. In bacteria, these enzymes can participate in primary metabolism and, notably, in antibiotic resistance by acetylating aminoglycoside antibiotics, reducing drug activity and contributing to resistance mechanisms.

Mechanistically, NATs mediate acetyl transfer through a direct SN2-like reaction, positioning the substrate amine for nucleophilic attack on the acetyl group of acetyl-CoA within a conserved active site. Due to their roles in drug metabolism, pharmacogenetics, and antimicrobial resistance, NATs are of ongoing interest in biomedical research.