Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition

Angélique Cocaign; Xavier Jean Philippe Kubiak; Ximing Xu; Guillaume Garnier; Inès Li de la Sierra-Gallay; Linh Chi-Bui; Julien Dairou; Florent Busi; Areej Abuhammad; Ahmed Haouz; Jean Marie Dupret; Jean Louis Herrmann; Fernando Rodrigues-Lima

doi:10.1107/s1399004714021282

Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition

Angélique Cocaign, Xavier Jean Philippe Kubiak, Ximing Xu, Guillaume Garnier, Inès Li de la Sierra-Gallay, Linh Chi-Bui, Julien Dairou, Florent Busi, Areej Abuhammad, Ahmed Haouz, Jean Marie Dupret, Jean Louis Herrmann, Fernando Rodrigues-Lima

Neuropharm and Genetics

5 Citations (Scopus)

Abstract

Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.

Original language	English
Journal	Acta crystallographica. Section D, Biological crystallography
Volume	70
Issue number	11
Pages (from-to)	3066-79
Number of pages	14
ISSN	0907-4449
DOIs	https://doi.org/10.1107/s1399004714021282
Publication status	Published - 1 Nov 2014

Access to Document

10.1107/s1399004714021282

Fingerprint

Dive into the research topics of 'Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition'. Together they form a unique fingerprint.

Cite this

Cocaign, A., Kubiak, X. J. P., Xu, X., Garnier, G., Li de la Sierra-Gallay, I., Chi-Bui, L., Dairou, J., Busi, F., Abuhammad, A., Haouz, A., Dupret, J. M., Herrmann, J. L., & Rodrigues-Lima, F. (2014). Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition. Acta crystallographica. Section D, Biological crystallography, 70(11), 3066-79. https://doi.org/10.1107/s1399004714021282

Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus : differences from other mycobacterial isoforms and implications for selective inhibition. / Cocaign, Angélique; Kubiak, Xavier Jean Philippe; Xu, Ximing et al.

In: Acta crystallographica. Section D, Biological crystallography, Vol. 70, No. 11, 01.11.2014, p. 3066-79.

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

Cocaign, A, Kubiak, XJP, Xu, X, Garnier, G, Li de la Sierra-Gallay, I, Chi-Bui, L, Dairou, J, Busi, F, Abuhammad, A, Haouz, A, Dupret, JM, Herrmann, JL & Rodrigues-Lima, F 2014, 'Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition', Acta crystallographica. Section D, Biological crystallography, vol. 70, no. 11, pp. 3066-79. https://doi.org/10.1107/s1399004714021282

Cocaign A, Kubiak XJP, Xu X, Garnier G, Li de la Sierra-Gallay I, Chi-Bui L et al. Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition. Acta crystallographica. Section D, Biological crystallography. 2014 Nov 1;70(11):3066-79. doi: 10.1107/s1399004714021282

Cocaign, Angélique ; Kubiak, Xavier Jean Philippe ; Xu, Ximing et al. / Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus : differences from other mycobacterial isoforms and implications for selective inhibition. In: Acta crystallographica. Section D, Biological crystallography. 2014 ; Vol. 70, No. 11. pp. 3066-79.

@article{38f649da9ba3403d8956633e7fdbf614,

title = "Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition",

abstract = "Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 {\AA} resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.",

author = "Ang{\'e}lique Cocaign and Kubiak, {Xavier Jean Philippe} and Ximing Xu and Guillaume Garnier and {Li de la Sierra-Gallay}, In{\`e}s and Linh Chi-Bui and Julien Dairou and Florent Busi and Areej Abuhammad and Ahmed Haouz and Dupret, {Jean Marie} and Herrmann, {Jean Louis} and Fernando Rodrigues-Lima",

year = "2014",

month = nov,

day = "1",

doi = "10.1107/s1399004714021282",

language = "English",

volume = "70",

pages = "3066--79",

journal = "Acta Crystallographica Section D: Structural Biology",

issn = "2059-7983",

publisher = "International Union of Crystallography",

number = "11",

}

TY - JOUR

T1 - Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus

T2 - differences from other mycobacterial isoforms and implications for selective inhibition

AU - Cocaign, Angélique

AU - Kubiak, Xavier Jean Philippe

AU - Xu, Ximing

AU - Garnier, Guillaume

AU - Li de la Sierra-Gallay, Inès

AU - Chi-Bui, Linh

AU - Dairou, Julien

AU - Busi, Florent

AU - Abuhammad, Areej

AU - Haouz, Ahmed

AU - Dupret, Jean Marie

AU - Herrmann, Jean Louis

AU - Rodrigues-Lima, Fernando

PY - 2014/11/1

Y1 - 2014/11/1

N2 - Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.

AB - Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.

U2 - 10.1107/s1399004714021282

DO - 10.1107/s1399004714021282

M3 - Journal article

C2 - 25372695

SN - 2059-7983

VL - 70

SP - 3066

EP - 3079

JO - Acta Crystallographica Section D: Structural Biology

JF - Acta Crystallographica Section D: Structural Biology

IS - 11

ER -