Structure-based design of novel inhibitors of 3-deoxy-D-manno-octulosonate 8-phosphate synthase.
3-Deoxy-D-manno-octulosonate 8-phosphate (KDO8P) is the phosphorylated precursor of KDO, an essential sugar of the lipopolysaccharide of Gram negative bacteria. KDO8P is produced by a specific synthase (KDO8PS) by condensing arabinose 5-phosphate (A5P) and phosphoenolpyruvate (PEP), with release of inorganic phosphate. As KDO8PS is present in bacteria and plants, but not in mammalian cells, and mutations that inactivate KDO8PS also block cell replication, KDO8PS is a promising target for the design of new antimicrobials that act by blocking lipopolysaccharide biosynthesis. Previous studies have shown that a compound mimicking an intermediate of the condensation reaction is a good ligand and a powerful inhibitor. Here we report on the crystallographic investigation of the binding to KDO8PS of new derivatives of this original inhibitor. The structures of the enzyme in complex with these compounds, and also with the PEP analogs, 2-phosphoglyceric acid (2-PGA) and Z-methyl-PEP, point to future strategies for the design of novel inhibitors of KDO8PS.
Xu
Xingjue
X
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, 48201 USA.
Wang
Jian
J
Grison
Claude
C
Petek
Sylvian
S
Coutrot
Philippe
P
Birck
Matthew R
MR
Woodard
Ronald W
RW
Gatti
Domenico L
DL
D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005988:Glyceric Acids / Q000737:chemistry; D006090:Gram-Negative Bacteria / Q000737:chemistry; D008958:Models, Molecular; D010728:Phosphoenolpyruvate / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013400:Sugar Acids / Q000737:chemistry
D005988:Glyceric Acids; D013400:Sugar Acids; C008885:2-phosphoglycerate; D010728:Phosphoenolpyruvate; C020011:2-dehydro-3-deoxyphosphooctonate aldolase; D000446:Aldehyde-Lyases; C120356:3-deoxy-manno-oct-2-ulopyranosonic acid