Sulfonamide-acetylating enzyme

Primary aromatic amine Hydrazines Sulfonamides (The enzyme and coenzyme catalyzing above reactions are N-acetyl transferase and acetyl coenzyme A.)... 

Acetylation may occur with -NHg, -OH, and -SH groups. Acetylation of primary aromatic amines and sulfonamide nitrogens are the most important of these reactions in the inactivation of drugs. These reactions occur in most laboratory and domestic animals. The dog is unable to acetylate aromatic amines or hydrazines, probably due to a lack of selective acetylating enzymes. Deacetylation of the conjugate may occur in certain species, e.g. the chicken de-acetylates aromatic amines, and dogs deacetylate aliphatic amino acids. Acetylation reactions have also been reported to occur in amphibia, fish, and a few insect species [20]. 

The extent to which a sulfonamide is acetylated depends upon the drug administered and the animal species. Acetylsulfathiazole is the principal metabolite found in the urine of cattle, sheep, and swine after enteral or parenteral administration of sulfathiazole. However, sheep can acetylate only 10% of the dose, while cattle can acetylate 32%, and swine 39%. When sulfamethazine was administered intravenously or orally to cattle, the animals eliminated 11% or 25% of the dose, respectively, in urine as N" -acetylsulfamethazine. The increased acetylation that occurred following tlie oral administration may be related to the increased exposure of sulfamethazine to liver enzymes following its absorption into the portal circulation. The acetylation rate may also be affected by the health status of an animal. Tims, cows suffering from ketosis in cows acetylate sulfonamides at much lower extent. 

Dmgs with amine and hydrazine groups may be conjugated to acetate (Sturgill and Lambert, 1997). Sulfonamides often undergo acetylation (Brown, 2001). A-acetyltransfer-ase is an enzyme in the cytoplasm involved in acetylation reactions. 

The effect of many structural modifications of acetazolamide has been reported. Substitution on the sulfonamide nitrogen destroys in vitro activity, but activity in animals may be retained if the substituent can be removed by metabolism (39). The absence of the acetyl from the amino group greatly reduces anti enzyme activity. Acyl groups higher than acetyl (65) retain in vitro activity and diuretic activity in animals and in man but may exhibit more pronounced side effects (26). Methylation (70) gives the two isomeric prod-... 

The drug is practically insoluble in water (1 g in 10,000 ml). Thus, being poorly absorbed from the small intestine, SZ reaches the colon intact, where bacterial azo-reductase enzymes cleave the compound to its components sulfapyridine (SP) and 5-aminosali-cylic acid (5-ASA). In slow acetylators, where the absorption of SP can lead to plasma levels above 50 pg/ml. It is very likely that it is the sulfonamide that is responsible for the toxic adverse effects associated with SZ. It is ironic that the drug s suppressive effect on ulcerative colitis was at first attributed to the local antibacterial effect of SP. With the dis-... 

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. 

Chloramphenicol acetyl transferase (CAT) enzyme substrates and products Sulfonamides... 

The mode of action of sulfonamides was greatly clarified by Woods in 1940. It had been shown that tissue extracts, pus, bacteria, and particularly yeast extract contained a heat-stable substance of low molecular weight which would inhibit the action of sulfonamides on bacteria (Stamp, 1939). Woods, recalling that enzymes are inhibited by substances which chemically and sterically resemble their substrates (see Section 9.3.1), adopted this hypothesis that the inhibitory substance in yeast is the substrate of an enzyme widely distributed in nature, and that it resembles sulfanilamide chemically. He found activity was concentrated in an alkali-soluble fraction of yeast, and that it ran parallel to a colour test for an aromatic amino-group. Activity was lost on esterification or acetylation, recovered on hydrolysis, and lost again on treatment with nitrous acid (Woods, 1940). Thus he made it clear that the active substance was an aromatic amino-acid. Because -aminobenzoic acid (/ AB) 2,12, p. 31) is the aromatic amino acid that most resembles sulfanilamide 2.13) he tried it as an inhibitor of bacteriostasis, and found that one molecule could prevent 5000 to 25 000 molecules of sulfanilamide from functioning. 

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