Structure of shikimate kinase, an in vivo essential metabolic enzyme in the nosocomial pathogen Acinetobacter baumannii, in complex with shikimate. (1st August 2015)

• Record Type: Journal Article
• Authors: Sutton, Kristin A.; Breen, Jennifer; MacDonald, Ulrike; Beanan, Janet M.; Olson, Ruth; Russo, Thomas A.; Schultz, L. Wayne; Umland, Timothy C.
• Is Part Of: Acta crystallographica. Volume 71:Part 8(2015:Aug.)
• Page Start: 1736
• Page End: 1744
• Publication Date: 2015-08-01
• Subjects: Biomolecules -- Structure -- Periodicals; Physical biochemistry -- Periodicals; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; 572
• DOI: 10.1107/S139900471501189X
• Languages: English
• ISSNs: 0907-4449

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <italic>Acinetobacter baumannii</italic> is an opportunistic Gram‐negative pathogen that is an important cause of healthcare‐associated infections exhibiting high mortality rates. Clinical isolates of multidrug‐resistant (MDR) and extremely drug‐resistant (XDR) <italic>A. baumannii</italic> strains are increasingly being observed. Compounding this concern is the dearth of new antibacterial agents in late‐stage development that are effective against MDR and XDR <italic>A. baumannii</italic>. As part of an effort to address these concerns, two genes (<italic>aroA</italic> and <italic>aroC</italic>) of the shikimate pathway have previously been determined to be essential for the growth and survival of <italic>A. baumannii</italic> during host infection (<italic>i.e.</italic> to be essential <italic>in vivo</italic>). This study expands upon these results by demonstrating that the <italic>A. baumannii aroK</italic> gene, encoding shikimate kinase (SK), is also essential <italic>in vivo</italic> in a rat soft‐tissue infection model. The crystal structure of <italic>A. baumannii</italic> SK in complex with the substrate shikimate and a sulfate ion that mimics the binding interactions expected for the β‐phosphate of ATP was then determined to 1.91 Å resolution and the enzyme kinetics were characterized. The flexible shikimate‐binding domain and LID region are compared with the analogous regions in other SK crystal structures. The impact of structural differences and sequence divergence between SKs from pathogenic bacteria that may influence antibiotic‐development efforts is discussed.</p> </abstract>