Acetylation, deacetylation and acyltransfer

Abstract

N -Substituted aromatic compounds can be metabolized in most species to N -acetylated derivatives that are themselves subject to further enzymatic transformations, including hydrolysis and N,O -acyltransfer. These proceses can either potentiate or ameliorate the biological responses to these N -substituted derivatives. Decreasing the levels of metabolites, such as arylhydroxylamines may, in some systems, reduce the probability of eliciting adverse biological effects. In others, arylhydroxamic acids produced by the acetylation of arylhydroxylamines may increase their potential for metabolic activation by N,O -acyltransfer. In the rabbit, rat and perhaps other species, the acetyl CoA-dependent N -acetyltransferase is also capable of activating arylhydroxamic acids by N-O -acyltransfer. These cytosolic organotriphosphate ester-resistant enzymes can utilize arylhydroxamic acid as a donor of the acetyl moiety in the acetyl transferase reaction and apparently are capable of activating arylhydroxamic acids because of their ability to O -acetylate the arylhydroxlamine. In mice, N -acetyltransferase and N,O -acetyltransferase seem not to exhibit this relationship. Enzymes from the microsomes of a number of species are also capable of activating arylhydroxamic acids. The particulate-bound enzymes are organotriphosphate ester-sensitive deacylases that are unable to form nucleic acid adducts on incubation with N -methoxy- N -acetylaminoarenes, substrates that are not capable of activation by N,O -acyltransfer. Thus, depending on the specificity of the enzymes involved, N -substituted aromatic compounds may be activated by N,O -acyltransfer during both the acetylation and deacylation process. The influence of this activation in the carcinogenic process is the object of continuing investigation.

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

“…Although the hydrolysis pathway was observed during in vitro experiments using dog liver S9 fractions, the nonreversible deacetylation of the B-ring acetamido group (Gao et al, 2006a) makes the metabolite more difficult to separate and detect in in vivo biological samples. The lack of N-acetyltransferase activity in dogs (King and Glowinski, 1983) was also responsible for our observation that the deacetylated metabolite M5 was observed in the dog, but not in the rat.…”

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

“…Although the hydrolysis pathway was observed during in vitro experiments using dog liver S9 fractions, the nonreversible deacetylation of the B-ring acetamido group (Gao et al, 2006a) makes the metabolite more difficult to separate and detect in in vivo biological samples. The lack of N-acetyltransferase activity in dogs (King and Glowinski, 1983) was also responsible for our observation that the deacetylated metabolite M5 was observed in the dog, but not in the rat.…”

N-hydroxyarylamine O-acetyltransferase of Salmonella typhimurium: proposal for a common catalytic mechanism of arylamine acetyltransferase enzymes.

“…(60). The catalytic mechanism of these enzymes is probably different from that proposed in Figure 4A.…”

N-Hydroxyarylamine O-Acetyltransferase of Salmonella typhimurium: Proposal for a Common Catalytic Mechanism of Arylamine Acetyltransferase Enzymes

“…One possible reason why the S. typhimurium OAT has a low N, O-acyltransferase activity is that an arylhydroxamic acid could not easily fit in the active site where the Cys69 probably resides. However, we must point out that certain N,O-acyltransferases have different properties from the OAT and NAT: some of the enzymes are located in microsomes and are sensitive to paraoxon (60). The catalytic mechanism of these enzymes is probably different from that proposed in Figure 4A.…”

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

“…Although the hydrolysis pathway was observed during in vitro experiments using dog liver S9 fractions, the nonreversible deacetylation of the B-ring acetamido group (Gao et al, 2006a) makes the metabolite more difficult to separate and detect in in vivo biological samples. The lack of N-acetyltransferase activity in dogs (King and Glowinski, 1983) was also responsible for our observation that the deacetylated metabolite M5 was observed in the dog, but not in the rat.…”

N-hydroxyarylamine O-acetyltransferase of Salmonella typhimurium: proposal for a common catalytic mechanism of arylamine acetyltransferase enzymes.

“…(60). The catalytic mechanism of these enzymes is probably different from that proposed in Figure 4A.…”

N-Hydroxyarylamine O-Acetyltransferase of Salmonella typhimurium: Proposal for a Common Catalytic Mechanism of Arylamine Acetyltransferase Enzymes

“…One possible reason why the S. typhimurium OAT has a low N, O-acyltransferase activity is that an arylhydroxamic acid could not easily fit in the active site where the Cys69 probably resides. However, we must point out that certain N,O-acyltransferases have different properties from the OAT and NAT: some of the enzymes are located in microsomes and are sensitive to paraoxon (60). The catalytic mechanism of these enzymes is probably different from that proposed in Figure 4A.…”

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

“…Although the hydrolysis pathway was observed during in vitro experiments using dog liver S9 fractions, the nonreversible deacetylation of the B-ring acetamido group (Gao et al, 2006a) makes the metabolite more difficult to separate and detect in in vivo biological samples. The lack of N-acetyltransferase activity in dogs (King and Glowinski, 1983) was also responsible for our observation that the deacetylated metabolite M5 was observed in the dog, but not in the rat.…”

N-hydroxyarylamine O-acetyltransferase of Salmonella typhimurium: proposal for a common catalytic mechanism of arylamine acetyltransferase enzymes.

“…(60). The catalytic mechanism of these enzymes is probably different from that proposed in Figure 4A.…”

N-Hydroxyarylamine O-Acetyltransferase of Salmonella typhimurium: Proposal for a Common Catalytic Mechanism of Arylamine Acetyltransferase Enzymes

“…One possible reason why the S. typhimurium OAT has a low N, O-acyltransferase activity is that an arylhydroxamic acid could not easily fit in the active site where the Cys69 probably resides. However, we must point out that certain N,O-acyltransferases have different properties from the OAT and NAT: some of the enzymes are located in microsomes and are sensitive to paraoxon (60). The catalytic mechanism of these enzymes is probably different from that proposed in Figure 4A.…”