ADP-heptose analogs
Abstract
Lipopolysaccharides are essential components of the outer leaflet of the bacterial cell membrane. Gene defects affecting the biosynthesis of the conserved inner-core region lead to decreased barrier performance, an increase in permeability for hdrophobic antibiotica and a reduced bacterial virulence. The proposal is focused on the chemical synthesis of native phosphorylated compounds and stable derivatives of bacterial heptoses. The synthetic compounds should contribute to a full understanding of the biosynthetic pathway involved in the assembly of the bacterial heptose region and will be tested for potential inhibitory properties. In preliminary experiments novel details concerning the structure of the native substrates for bacterial heptosyl transferases could be obtained. Since the physiological substrate - a heptosyl nucleoside diphosphate - is rather unstable, stable analogs will be synthesized by either substituting the glycosidic oxygen by stable C-aglycons or by replacing the 2-OH group of the heptose unit with azide, fluorine or hydrogen substituents. The compounds will be transformed into phosphonic acid and phosphoric acid derivatives and subsequently converted into the nucleotide-activated sugars. The compounds will also be useful for biochemical studies of the other 5 key enzymes involved in the biosynthesis of heptose, such as a novel putative kinase- and phosphatase reaction as well as the nucleotide-heptose-synthase and epimerase reaction. The latter enzyme has recently be crystallized and the x-ray structure has been determined. Employing the synthetic compounds, the determination of the crystal structures of the enzyme-substrate and enzyme product complexes will be attempted. The data to be obatined on the binding process and the reaction mechanism in the active site of the enzyme should provide a reasonable model for the rational design of inhibitors as novel lead compounds in antibacterial drug research.
dx.doi.orgProject staff
Paul Kosma
Univ.-Prof. i.R. Dipl.-Ing.Dr.techn. Paul Kosma
paul.kosma@boku.ac.at
Tel: +43 1 47654-77355
Project Leader
15.09.2001 - 14.09.2005
BOKU partners
External partners
Forschungszentrum Borstel
none
partner
University of Western Ontario
M. Valvano
partner
Laboratory of Biochemistry and Genetics National Institute of Diabetes and Kidney Diseases National Institute of Health
none
partner