Arylamine NATs

Arylamine NATs are a family of DMEs that catalyze the conjugation of an acetyl group from acetyl-coenzyme A to the terminal amino group of arylamines,... 

J. Massengill, K.E. Anderson, M.D. Gross, Influence of NAT-1 Genotype on NAT-2 Phenotype , First International Workshop on the Arylamine N-Acetyltransjerases, Cairns, Australia, October, 22-24,1998. 

The N-acetyl transferase (NAT) polymorphism is one of the earliest pharmacogenetic targets recognized and characterized. NATs are Phase II enzymes that catalyze the transfer. of an acetyl moiety from acetyl-CoA to homocychc and heterocyclic arylamines and hydrazines. Substrates include drugs, carcinogens, toxicants, and possibly endogenous compounds. Slow metabolizer phenotypes, which may affect up to 90% of some populations, are manifested by changes in protein expression, protein stability, and enzyme kinetics. 

Studies with additional substrates for NAT demonstrated that the phenotype was not relevant to all substrates. For example, the NAT phenotype was clearly recognized for arylamines such as isoniazid, some sulfonamides, amrinone, dapsone, procainamide, caffeine, and clonazepam. The phenotype was not observed with other arylamine substrates such as p-aminobenzoate (PABA) and p-aminosahcylate (PAS). A folate catabolite, p-aminobenzoylglutamate, is the only endogenous NAT substrate proposed. Flowever, NAT2 knock-out and NATl and NAT2 double knock-out mice do not express phenotypical abnormalities, suggesting that these enzymes are not required for development or function. ... 

Anonymous. Arylamine N-Acetyltransferase (NAT) Nomenclature, http //www.louisville.edu/med-school/pharmacology/NAT.html (Accessed December 5, 2004). 

Acetylation Reactions. The major enzyme system catalyzing acetylation reactions is arylamine N-acetyltransferase (arylamine acetylase EC 2.3.1.5 NAT). Two enzymes have been characterized, NATl and NAT2 the latter has two closely related isoforms NAT2A and NAT2B whose levels are considerably reduced in the liver of slow acetylators (68,69). The cofactor of AT-acetyltransferase is acetylcoenzyme A (CoA-S-Ac, 29 with R = acetyl) (Fig. 13.24) where the acetyl moiety is bound by a thioester linkage. 

NATs are also involved in bioactivation reactions via O-acetylation of Y-hydroxylamines formed from CYP-mediated N-hydroxylation of arylamines. These bioactivation reactions form unstable acetoxy esters that decompose to highly reactive species, which bind to cellular DNA [83], The O-sulfonation of compounds catalyzed by SULTs can also result in the formation reactive intermediates. Recently, it has been shown that a-hydroxytamoxifen (derived from CYP-mediated hydroxy-lation of tamoxifen) is bioactivated by SULTs [177],... 

Arylamine N-acetyltransferases (NAT) are highly conserved in eukaryotes. These cytosolic enzymes transfer acetate from acetylCoA to primary amines, hydrazines, sulfonamides, and aromatic amines. They are 30 to 34 kDa in size. Humans express two functional NATs, NATl and NAT2. The genes for both isoforms encode 290 amino acids, and are found on chromosome 8. Their nucleotide sequences share 87% homology. These enzymes exhibit polymorphism, and allelic variation especially for NAT2 is associated with fast and slow acetylator phenotypes. 

The most common reactions of acylation are in fact acetylations of xenobiotics containing a primary amino group. The cofactor of acetylation is acetylcoenzyme A (acetyl-S-CoA), the reaction being catalysed by a variety of A-acetyltransferases. Arylamine Af-acetyltransferases (NAT-1 and -2) are the most important enzyme, but aromatic-hydroxylamine O-acetyltransferase and N-hydroxyarylamine >-acetyltransferase are also involved in the acetylation of some aromatic amines and hydroxyl-amines. 

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