The Bacillus anthracis arylamine N-acetyltransferase ((BACAN)NAT1) that inactivates sulfamethoxazole, reveals unusual structural features compared with the other NAT isoenzymes

Benjamin Pluvinage; Inés Li de la Sierra-Gallay; Xavier Jean Philippe Kubiak; Ximing Xu; Julien Dairou; Jean-Marie Dupret; Fernando Rodrigues-Lima

doi:10.1016/j.febslet.2011.10.041

The Bacillus anthracis arylamine N-acetyltransferase ((BACAN)NAT1) that inactivates sulfamethoxazole, reveals unusual structural features compared with the other NAT isoenzymes

Benjamin Pluvinage, Inés Li de la Sierra-Gallay, Xavier Jean Philippe Kubiak, Ximing Xu, Julien Dairou, Jean-Marie Dupret, Fernando Rodrigues-Lima

Department of Neuroscience

18 Citations (Scopus)

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.

Original language	English
Journal	F E B S Letters
Volume	585
Issue number	24
Pages (from-to)	3947-52
Number of pages	6
ISSN	0014-5793
DOIs	https://doi.org/10.1016/j.febslet.2011.10.041
Publication status	Published - 15 Dec 2011

Keywords

Amino Acid Sequence
Animals
Arylamine N-Acetyltransferase
Bacillus anthracis
Coenzyme A
Crystallography, X-Ray
Humans
Isoenzymes
Models, Molecular
Molecular Sequence Data
Protein Structure, Tertiary
Sulfamethoxazole
Xenobiotics

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Pluvinage, B., Li de la Sierra-Gallay, I., Kubiak, X. J. P., Xu, X., Dairou, J., Dupret, J-M., & Rodrigues-Lima, F. (2011). The Bacillus anthracis arylamine N-acetyltransferase ((BACAN)NAT1) that inactivates sulfamethoxazole, reveals unusual structural features compared with the other NAT isoenzymes. F E B S Letters, 585(24), 3947-52. https://doi.org/10.1016/j.febslet.2011.10.041

The Bacillus anthracis arylamine N-acetyltransferase ((BACAN)NAT1) that inactivates sulfamethoxazole, reveals unusual structural features compared with the other NAT isoenzymes. / Pluvinage, Benjamin; Li de la Sierra-Gallay, Inés; Kubiak, Xavier Jean Philippe et al.

In: F E B S Letters, Vol. 585, No. 24, 15.12.2011, p. 3947-52.

Research output: Contribution to journal › Journal article › Research › peer-review

Pluvinage, B, Li de la Sierra-Gallay, I, Kubiak, XJP, Xu, X, Dairou, J, Dupret, J-M & Rodrigues-Lima, F 2011, 'The Bacillus anthracis arylamine N-acetyltransferase ((BACAN)NAT1) that inactivates sulfamethoxazole, reveals unusual structural features compared with the other NAT isoenzymes', F E B S Letters, vol. 585, no. 24, pp. 3947-52. https://doi.org/10.1016/j.febslet.2011.10.041

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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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AU - Li de la Sierra-Gallay, Inés

AU - Kubiak, Xavier Jean Philippe

AU - Xu, Ximing

AU - Dairou, Julien

AU - Dupret, Jean-Marie

AU - Rodrigues-Lima, Fernando

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N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Arylamine N-Acetyltransferase

KW - Bacillus anthracis

KW - Coenzyme A

KW - Crystallography, X-Ray

KW - Humans

KW - Isoenzymes

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Protein Structure, Tertiary

KW - Sulfamethoxazole

KW - Xenobiotics

U2 - 10.1016/j.febslet.2011.10.041

DO - 10.1016/j.febslet.2011.10.041

M3 - Journal article

C2 - 22062153

SN - 0014-5793

VL - 585

SP - 3947

EP - 3952

JO - F E B S Letters

JF - F E B S Letters

IS - 24

ER -

The Bacillus anthracis arylamine N-acetyltransferase ((BACAN)NAT1) that inactivates sulfamethoxazole, reveals unusual structural features compared with the other NAT isoenzymes

Abstract

Keywords

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