Chemical and Structural Insights into the Regioversatility of the Aminoglycoside Acetyltransferase Eis. Issue 16 (17th September 2013)

• Record Type: Journal Article
• Authors: Houghton, Jacob L.; Biswas, Tapan; Chen, Wenjing; Tsodikov, Oleg V.; Garneau‐Tsodikova, Sylvie
• Is Part Of: Chembiochem. Volume 14:Issue 16(2013)
• Page Start: 2127
• Page End: 2135
• Publication Date: 2013-09-17
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201300359
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A recently discovered cause of tuberculosis resistance to a drug of last resort, the aminoglycoside kanamycin, results from modification of this drug by the enhanced intracellular survival (Eis) protein. Eis is a structurally and functionally unique acetyltransferase with an unusual capability of acetylating aminoglycosides at multiple positions. The extent of this regioversatility and its defining protein features are unclear. Herein, we determined the positions and order of acetylation of five aminoglycosides by NMR spectroscopy. This analysis revealed unprecedented acetylation of the 3′′‐amine of kanamycin, amikacin, and tobramycin, and the γ‐amine of the 4‐amino‐2‐hydroxybutyryl group of amikacin. A crystal structure of Eis in complex with coenzyme A and tobramycin revealed how tobramycin can be accommodated in the Eis active site in two binding modes, consistent with its diacetylation. These studies, describing chemical and structural details of acetylation, will guide future efforts towards designing aminoglycosides and Eis inhibitors to overcome resistance in tuberculosis.</p> </abstract>