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Aminoglycoside N-Acetyltransferases

The Aminoglycoside N-Acetyltransferases (AAC) family of enzymes is composed of four major subclasses based on regiospecificity of aminoglycoside acetyltransfer: AAC(6 ), AAC(2 ), AAC(1), and AAC(3). These enzymes are found in both Gram-positive and Gram-negative bacteria and generally present a very broad aminoglycoside resistance profile. The AACs form the largest family of aminoglycoside resistance enzymes and are dominated by the large number of AAC(6 ) homologs, many of which are chromosomally encoded.

The crystal structure of AACs enzymes reveal their similarity to one another and their affiliation with the GCN5-related N-acetyltransferases (GNAT) superfamily [1]. The family is defined by a common 3D-folding pattern formed around an acyl-CoA binding pocket. The AAC enzymes share little amino acid sequence homology with other members of the GNAT superfamily such as the histone acetyltransferases. However, they share the folding motifs that define this family: an N-terminal α-helix, a central antiparallel β-sheet, and a four stranded mixed b-sheet flanked by two a-helices at the C-terminus.
The aminoglycoside-binding pocket is quite plastic and able to accommodate numerous substrates. The continued evolution of the class is exemplified by the reported ability of a variant of AAC(6 )-Ib, AAC(6 )-Ib-cr, to modify the synthetic fluoroquinolone antibiotic ciprofloxacin (Scheme 1.) [2].

 

 

 


1. Vetting, M. W.; de Carvalho LP, S. d. C.; Yu, M.; Hegde, S. S.; Magnet, S.; Roderick, S. L.; Blanchard, J. S. Arch. Biochem. Biophys. 2005, 433, 212.

2. Robicsek, A.; Strahilevitz, J.; Jacoby, G. A.; Macielag, M.; Abbanat, D.; Park, C. H.; Bush, K.; Hooper, D. C. Nat. Med. 2006, 12, 83.

 

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