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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1e2t

E.C. nameN-hydroxyarylamine O-acetyltransferase
SpeciesSalmonella typhimurium (Bacteria)
E.C. Number (IntEnz) 2.3.1.118
CSA Homologues of 1e2tThere are 14 Homologs
CSA Entries With UniProtID Q00267
CSA Entries With EC Number 2.3.1.118
PDBe Entry 1e2t
PDBSum Entry 1e2t
MACiE Entry 1e2t

Literature Report

IntroductionThe N acetyl-transferase (NAT) family of enzymes N-acetylate arlyhydrazines and arylamines. The transfer of an acetyl group from acetyl coenzyme A to a substrate was first noted in the deactivation of the drug isonizid, where the rate of deactivation varied between individuals, as explained by pharmacogenetic variation in the rate of NAT activity. NAT enzymes are also involved in the metabolism and detoxification of arylamine and arylhydroxylamine carcinogenic substrates.
MechansimThe N-acetylation mechanism involves the transfer of an acetyl group from acetyl coenzyme A to the aryl substrate. The main catalytic residue, Cys 69 has been shown to form a reactive acyl-enzyme intermediate which is readily deacetylated by the basic N atom of the amine substrate. The close proximity Arg 64, along with the conserved Glu 39 are thought to stabilise the conformation of the Cys 69, and are not involved in a general base activation mechanism at Cys 69 as has been suggested in some work. The low pKa of Cys 69 associated with the formation of a nucleophilic thiolate at physiological pH levels results in a highly activated acetyl- enzyme intermediate (the lower the pKa, the more stable the conjugate acid).

Reaction

Catalytic Sites for 1e2t

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluA3939macie:sideChainThe residue acts to stabilise the conformation of the catalytic Cys 69 through the salt bridge formed with Arg 64, which is close in proximity to the catalytic residue.
CysA6969macie:sideChainThe catalytic Cys 69 exists as a thiolate at physiological pH level. It acts as a nucleophile towards the acetyl coenzyme A initially forming an acetyl-enzyme intermediate. The low pKa of the thiol group increases the activity of the associated thioester, which increases its susceptibility towards nucleophilic attack of the arylamine or arylhydroxylamine substrate.
ArgA6464macie:sideChainThe residue acts to stabilise the conformation of the catalytic Cys 69 through the salt bridge formed with the conserved Glu 39 residue. The residue is remote in space from the catalytic S atom of Cys 69 and so does not act as a general base to activate nucleophilic attack.

Literature References

Notes:
Sinclair JC
Structure of arylamine N-acetyltransferase reveals a catalytic triad.
Nat Struct Biol 2000 7 560-564
PubMed: 10876241
Andres HH
On the active site of liver acetyl-CoA. Arylamine N-acetyltransferase from rapid acetylator rabbits (III/J).
J Biol Chem 1988 263 7521-7527
PubMed: 2897358
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