Nacetyltransferases

N-acetyltransferases are enzymes that catalyze the transfer of an acetyl group from acetyl-CoA to an amine or arylamine substrate, forming an acetamide. They participate in the metabolism of drugs, xenobiotics, and certain endogenous compounds. Most characterized NATs belong to the GCN5-related N-acetyltransferase (GNAT) superfamily, a broad group with a conserved fold featuring a central beta-sheet flanked by helices. The GNAT enzymes exhibit a wide range of substrate specificities, reflecting evolutionary diversification.

In humans, the best known NATs are NAT1 and NAT2, both cytosolic enzymes involved in xenobiotic metabolism. NAT2 displays genetic polymorphism resulting in fast, intermediate, or slow acetylator phenotypes, which influence individual responses to certain medications (such as isoniazid and caffeine) and to carcinogenic arylamines. NAT1 has a broader tissue distribution and substrate scope, though clinical implications are less precisely defined.

In bacteria, N-acetyltransferases contribute to antibiotic resistance by acetylating aminoglycoside antibiotics, diminishing their binding to ribosomal targets. Aminoglycoside N-acetyltransferases (AACs), including AAC(3) and AAC(6') variants, modify drugs at specific amine sites and can confer resistance to multiple antibiotic classes. Other bacterial NATs participate in the modification of amino compounds and metabolism.

Structural and mechanistic features common to NATs include a conserved acetyl-CoA binding site and a substrate-binding pocket that aligns the acceptor amine for acetyl transfer. Catalysis typically involves deprotonation of the amine and transfer of the acetyl group to form the acetamide product and CoA.

N-acetyltransferases are studied as models of enzyme evolution, determinants of drug metabolism, and potential targets for strategies to overcome resistance.