A-Acetyltransferase

A/-acetyltransferase 2 Low activity in about 60% of Caucasian populations. High incidence of adverse events from the drug isoniazide in slow acetylators. 

Similarly, polymorphisms on the A -acetyltransferase 1 and 2 genes (NATl, NAT2) that encode the enzymes responsible for inactivating 5-aminosalicylate and sulfapyridine did not influence response to therapy or toxicity (46). 

Genes encoding a nourseothricin A-acetyltransferase confer resistance to aminoglycosides... 

This enzyme [EC 2.3.1.1], also referred to as amino-acid A-acetyltransferase and acetyl-CoA glutamate N-acetyltransferase, catalyzes the reaction of acetyl-CoA with glutamate to form coenzyme A and A-acetylgluta-mate. The enzyme will also acts on aspartate and, more slowly, with some other amino acids. The mammalian enzyme is activated by L-arginine. See also Glutamate Acetyltransferase... 

This enzyme [EC 2.3.1.5], also known as acetyl-CoA arylamine A-acetyltransferase and arylamine acetylase, catalyzes the reaction of acetyl-CoA with an arylamine to produce coenzyme A and an A-acetylarylamine. This enzyme exhibits a low specificity with respect to the aromatic amine substrate. In fact, even serotonin can serve as a substrate. The enzyme has also been reported to catalyze acetyl-transfer reactions between arylamines without the use of coenzyme A. 

As their name implies, the A-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. Examples of this type of reaction are depicted in Figure 4.1. The net result of this conjugation is an increase in water solubility and increased elimination of the compound. The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2. Little overlap in substrate specificities of the two isoforms appears to exist. NAT-2 is a polymorphic enzyme, a... 

The plasma half-life of hydralazine may be increased fourfold or fivefold in patients with renal failure. If renal failure is present, therefore, both the antihypertensive and toxic effects of hydralazine may be enhanced. Since A-acetylation of hydralazine is an important metabolic pathway and depends on the activity of the enzyme A-acetyltransferase, genetically determined differences in the activity of this enzyme in certain individuals (known as slow acetylators) wih result in higher plasma levels of hydralazine therefore, the drug s therapeutic or toxic effects may be increased. 

Kinzig-Schippers M et al Should we use A/-acetyltransferase type 2 genotyping to personalize isoniazid doses Antimicrob Agents Chemother 2005 49 1733. [PMID 15855489]... 

Figure 7.1 Some of the possible routes of metabolic activation of AAF. Abbreviations-. AAF, acetylamino-fluorene N-OH-AF, /V-hydroxyaminofluorene N-OH-AAF, /V-hydroxyacetylaminofIuorene A/-acetoxy AF, N-acetoxyaminofluorene N-(dG-8yl)-AF, AAdeoxyguanosinyl-aminof I uo rene N-(dG-8yl)-AAF, A/-deoxyguanosinyl-acety-laminofluorene P-450, cytochrome(s) P-450 DA, deacetylase NAT, A/-acetyltransferase AHAT, N, O-arylhydroxamic acid acyltransferase.

G.N. Levy, W.W. Weber, Interindividual Variability of A -Acetyltransferases in Man , in Interindividual Variability in Drug Metabolism in Man, eds. G. Pacifici, O. Pelkonen, Taylor and Francis, London, in press. 

Grant DM, Blum M, Beer M, Meyer UA. Monomorphic and polymorphic human arylamine A-acetyltransferases a comparison of liver isozymes and expressed products of two cloned genes. Mol Pharm 1991 39 184-191. 

A His residue is often found at the active site of enzymes where it functions as a catalyst in acid-base and nucleophilic processes. Substitution of fluorine on His reduces the pKa by about 5 pH units, and this dramatic drop in basicity is reflected in altered biological properties of FHis-containing proteins. The presence of 2-FHis in cell cultures inhibits the stimulation of several enzymes, for example, the stimulation of pineal gland A-acetyltransferase activity, in cell culture and in vivo. This stimulation is accompanied by His and cyclohex-imide-sensitive incorporation of 2-FHis into cellular protein192,193. A direct comparison of His and 2-F-His in mouse L cells showed that the analogue is incorporated at about 17% the efficiency of the parent194.4-FHis showed none of the above biological activity. 

Two cytoplasmic A-acetyltransferases, NAT1 and NAT2, have been identified in humans. N ATI is rather ubiquitous in its expression, whereas N AT2 is associated with the liver and the gastrointestinal tract. These enzymes have different but overlapping substrate preferences. A third enzyme, NAT3, has been identified in mouse. 

Acetylation by A-acetyltransferase occurs frequently with primary and secondary amines (e.g. sulphadiazine) and substituted hydrazines (e.g. isoniazid and hydralazine) the A-monoacetyl derivatives are usually produced. 

Figure 16 Acetylation of aniline by acetyl CoA A/-acetyltransferase activity.

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