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Acta Crystallogr D Biol Crystallogr. 2014 Nov;70(Pt 11):3066-79. doi: 10.1107/S1399004714021282. Epub 2014 Oct 29.

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

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Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, 75013 Paris, France.
EA 3647, Université Versailles St Quentin en Yvelines, Garches, France.
Université Paris-Sud, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, CNRS UMR 8619, 91405 Orsay, France.
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, England.
Institut Pasteur, Plateforme 6, CNRS-URA2185, 25 Rue du Dr Roux, 75724 Paris, France.


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.


Mycobacterium abscessus; arylamine N-acetyltransferase

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