Abstract
The bifunctional diaminohydroxyphosphoribosylaminopyrimidine deaminase/5-amino-6-(5-phosphoribosylamino)uracil reductase (RibD) represents a potential antibacterial drug target. The structure of recombinant Acinetobacter baumannii RibD is reported in orthorhombic and tetragonal crystal forms at 2.2 and 2.0 Å resolution, respectively. Comparisons with orthologous structures in the Protein Data Bank indicated close similarities. The tetragonal crystal form was obtained in the presence of guanosine monophosphate, which surprisingly was observed to occupy the adenine-binding site of the reductase domain.
Highlights
Acinetobacter species are a significant and increasingly important cause of hospital-acquired infections (Gaynes & Edwards, 2005), owing in part to a remarkable ability to resist antibiotic challenge (Peleg et al, 2008)
We identified that several genes encoding enzymes in the riboflavinbiosynthetic pathway are essential in Gram-negative bacteria such as P. aeruginosa
A highly efficient E. coli recombinant expression system for A. baumannii RibD (AbRibD) was constructed and a purification protocol was established that provided in excess of 100 mg per litre of culture
Summary
Acinetobacter species are a significant and increasingly important cause of hospital-acquired infections (Gaynes & Edwards, 2005), owing in part to a remarkable ability to resist antibiotic challenge (Peleg et al, 2008). We identified that several genes encoding enzymes in the riboflavinbiosynthetic pathway are essential in Gram-negative bacteria such as P. aeruginosa (see, for example, Liberati et al, 2006) This was supported by single gene knockout studies in the closely related A. baylyi (de Berardinis et al, 2008). Animals rely on dietary sources to acquire riboflavin, while bacteria generally synthesize it de novo. This essential aspect of bacterial metabolism is absent in mammals and suggests that this biosynthetic pathway might represent a potential source of antimicrobial drug targets (Mack & Grill, 2006; Long et al, 2010). We selected a bifunctional enzyme, diaminohydroxyphosphoribosylaminopyrimidine deaminase (EC 3.5.4.26)/5-amino-6-(5-phosphoribosylamino)uracil reductase (EC 1.1.1.193), called RibD, in this pathway as a potential target in Gram-negative bacteria
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