The Bacillus anthracis arylamine N-acetyltransferase ((BACAN)NAT1) that inactivates sulfamethoxazole, reveals unusual structural features compared with the other NAT isoenzymes |
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Authors: | Pluvinage Benjamin Li de la Sierra-Gallay Inés Kubiak Xavier Xu Ximing Dairou Julien Dupret Jean-Marie Rodrigues-Lima Fernando |
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Institution: | aUniv. Paris Diderot, Sorbonne Paris Cité, Unité BFA, EAC-CNRS 4413, 75013 Paris, France;bInstitut de Biologie Physico-Chimique, CNRS FRC550, 75005 Paris, France |
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Abstract: | Arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes that biotransform arylamine drugs. The Bacillus anthracis (BACAN)NAT1 enzyme affords increased resistance to the antibiotic sulfamethoxazole through its acetylation. We report the structure of (BACAN)NAT1. Unexpectedly, endogenous coenzymeA was present in the active site. The structure suggests that, contrary to the other prokaryotic NATs, (BACAN)NAT1 possesses a 14-residue insertion equivalent to the “mammalian insertion”, a structural feature considered unique to mammalian NATs. Moreover, (BACAN)NAT1 structure shows marked differences in the mode of binding and location of coenzymeA when compared to the other NATs. This suggests that the mechanisms of cofactor recognition by NATs is more diverse than expected and supports the cofactor-binding site as being a unique subsite to target in drug design against bacterial NATs. |
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Keywords: | Abbreviations: NAT arylamine N-acetyltransferase SMX sulfamethoxazole 3&prime ADP 3&prime adenosine diphosphate 5AS 5-aminosalycilic acid AcCoA acetyl Coenzyme A CoA coenzyme A PPi pyrophosphate |
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