N-acetyltransferase 2 NAT

The N-acetyltransferase (NAT) enzymes have been most highly characterized in humans for the historical reason that isoniazid/ a NAT substrate/ has played... 

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

For CES, there appear to be no regional differences in the small intestine for the N-acetyltransferase (NAT) activity [108]. The presence ofboth NAT isozymes has been demonstrated in the human gut mucosa by using the prototypical substrates p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) [109, 110]. The active metabolites 5-aminosalicylic acid and sulfapyridine of the prodrug sulfasalazine undergo extensive presystemic acetylation in the small intestine [111]. 

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. 

N-acetyltransferases (NATs) that have been implicated with the emergence of sulfonamides hypersensitivity and the toxicity observed in some cases of isoniazid, procainamide, and hydralazine administration [27]. 

In a comparison experiment, the possibility that vitamin C and P-carotene could affect PhIP-DNA adduct formation has been examined. Previous reports have already demonstrated the protective role of vitamin C in certain types of cancer and low intake of foods rich in vitamin C is associated with an increased risk of gastric cancer [100]. Vitamin C prevents DNA adduct formation in mice treated with the mycotoxins ochratoxin A and zearalenone [101]. Wu et al. [102] reported that vitamin C inhibited aiylamine N-acetyltransferase (NAT) activity in human bladder tumor cells. This is one possible mechanism by which vitamin C can attenuate the formation of DNA adducts. It... 

Figure 4.69 Metabolism of the carcinogen benzidine showing oxidation and acetylation. Both routes of acetylation can give rise to a reactive nitrenium ion and DNA adducts. Abbreviation. NAT, N-acetyltransferase.

CYP = cytochrome P450 isoenzyme NAT = N-acetyltransferase P-CP = P-glycoprotein PM, glue = phase II glucuronidation. PMs = poor metabolizers EMs = extensive metabolizers SAs = slow acetylators FAs = fast acetylators. 

As inhibitors of N-acetyltransferase activity, the formamidines showed a pattern similar to their effect on 0A uptake i.e. CDM was the least active member of the series with DCDM and DDCDM increasingly more active. At 0.25 mM, DDCDM caused about 50% inhibition of NAT activity. Little previous work has been published on N-acetyl transferase inhibitors in insects. However, the inhibition by CDM of NAT acting on tryptamine was reported by Allais et al. (29). They showed that 1.2 mg of CDM applied topically to locusts reduced subsequent NAT activity in the brain in vitro by approximately 35%. 

FIGURE 7.1 Some of the possible routes of metabolic activation of acetylaminofluorene (AAF). N-OH-AF N-hydroxyaminofluorene N-OH-AAF N-hydroxyacely/aminqfluorene N-acetoxy AF H-acetoxyaminofluorene N-(dG-8yl)-AF N-deoxyguanosinyl-aminofluorene N-(dG-8yl)-AAF N-deoxyguanosinyl-acetylaminofluorene. P-450 cytochrome(s) P-450 DA deacetylase NAT N-acetyltransferase AHAT N, O-arylhydroxamic acid acyltransferase. 

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. 

F. Javid-Majd, J.S. Blanchard, S.L. Roderick, Aminoglycoside 2 -N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates, Nat. Struct. Biol. 2002, 9, 653-658. 

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. 

Abbreviations Ac-NAT, acetyl-N-acetyltransferase NEM, N-ethyl maleimide INH, isoniazid. 

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