4GUZ

Structure of the arylamine N-acetyltransferase from Mycobacterium abscessus

Summary for 4GUZ

• Entry DOI: 10.2210/pdb4guz/pdb
• Descriptor: Probable arylamine n-acetyl transferase (2 entities in total)
• Functional Keywords: acetyltransf_2 transferase, acetyltransferase, acetyl coenzymea, cytosol, transferase
• Biological source: Mycobacterium abscessus
• Total number of polymer chains: 4
• Total formula weight: 126923.36

Authors

Kubiak, X.,Li de la Sierra-Gallay, I.,Haouz, A.,Weber, P.,Rodrigues-Lima, F. (deposition date: 2012-08-30, release date: 2013-10-23, Last modification date: 2023-09-13)

Primary citation

Cocaign, A.,Kubiak, X.,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.
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 Crystallogr.,Sect.D, 70:3066-3079, 2014

PubMed 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.

PubMed: 25372695
DOI: 10.1107/S1399004714021282

Experimental method

X-RAY DIFFRACTION (1.8 Å)