Article

Crystal structures of two putative phosphoheptose isomerases

Biology Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
Proteins Structure Function and Bioinformatics (Impact Factor: 2.92). 06/2006; 63(4):1092-6. DOI: 10.1002/prot.20908
Source: PubMed
0 Followers
 · 
70 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Heptoses are found in the surface polysaccharides of most bacteria, contributing to structures that are essential for virulence and antibiotic resistance. Consequently, the biosynthetic enzymes for these sugars are attractive targets for novel antibiotics. The best characterized biosynthetic enzyme is GmhA, which catalyzes the conversion of sedoheptulose-7-phosphate into D-glycero-D-manno-heptopyranose-7-phosphate, the first step in the biosynthesis of heptose. Here, the structure of GmhA from Burkholderia pseudomallei is reported. This enzyme contains a zinc ion at the heart of its active site: this ion stabilizes the active, closed form of the enzyme and presents coordinating side chains as a potential acid and base to drive catalysis. A complex with the product demonstrates that the enzyme retains activity in the crystal and thus suggests that the closed conformation is catalytically relevant and is an excellent target for the development of therapeutics. A revised mechanism for the action of GmhA is postulated on the basis of this structure and the activity of B. pseudomallei GmhA mutants.
    Journal of Molecular Biology 05/2010; 400(3):379-92. DOI:10.1016/j.jmb.2010.04.058 · 3.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The crystal structure of the H. influenzae YfeU protein, was determined at 1.90 A resolution using multi-wavelength anomalous diffraction. YfeU belongs to a very large conserved family of proteins found mainly in bacteria but also in archaea and eukaryota. The protein is a homolog of eukaryotic glucokinase regulator and is predicted to be a sugar phosphate isomerase or aminotransferase. Here we describe the structure of YfeU and discuss the possible function as an etherase possibly involved in peptidoglycan recycling.
    Journal of Structural and Functional Genomics 03/2009; 10(2):151-6. DOI:10.1007/s10969-009-9063-1
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: L-Heptoses (L-glycero-D-manno-heptopyranoses) are constituents of the inner core of lipolysaccharide (LPS), a molecule playing key roles in the mortality of many infectious diseases as well as in the virulence of many human pathogens. The inhibition of the first enzymes of the bacterial heptose biosynthetic pathway is an almost unexplored field to date although it appears to be a very novel way for the development of antivirulence drugs. We report the synthesis of a series of D-glycero-D-manno-heptopyranose 7-phosphate (H7P) analogues and their inhibition properties against the isomerase GmhA and the the kinase HldE, the two first enzymes of the bacterial heptose biosynthetic pathway. The heptose structures have been modified at the 1-, 2-, 6- and 7-positions to probe the importance of the key structural features of H7P that allow a tight binding to the target enzymes; H7P being the product of GmhA and the substrate of HldE, the second objective was to find structures that could simultaneously inhibit both enzymes. We found that GmhA and HldE were extremely sensitive to structural modifications at the 6- and 7- positions of the heptose scaffold. To our surprise, the epimeric analogue of H7P displaying a D-glucopyranose configuration was found to be the best inhibitor of both enzymes but also the only molecule of this series that could inhibit GmhA (IC(50)=34 μM) and HldE (IC(50)=9.4 μM) in the low micromolar range. Noteworthy, this study describes the first inhibitors of GmhA ever reported, and paves the way to the design of a second generation of molecules targeting the bacterial virulence.
    Chemistry - A European Journal 09/2011; 17(40):11305-13. DOI:10.1002/chem.201100396 · 5.70 Impact Factor

Preview

Download
0 Downloads
Available from