Synthesis and evaluation of tetrahedral intermediate mimic inhibitors of 3-deoxy-d-manno-octulosonate 8-phosphate synthase.
3-Deoxy-d-manno-octulosonate 8-phosphate (KDO8P) synthase catalyses the first committed step in the biosynthesis of 3-deoxy-d-manno-octulosonate (KDO), an important component of the lipopolysaccharide of Gram-negative bacteria. The pathway for KDO biosynthesis has been identified as a potential target of antibacterial drug design. The reaction catalysed by KDO8P synthase is an aldol-like condensation between phosphoenolpyruvate (PEP) and d-arabinose 5-phosphate (A5P) and proceeds through a bisphosphorylated tetrahedral intermediate. In this study a bisphosphate analogue of the tetrahedral intermediate was synthesised and was found to inhibit the metal-dependent KDO8P synthase from Neisseriameningitidis and the metal-dependent KDO8P synthase from Acidithiobacillus ferrooxidans with inhibition constants in the low micromolar range. Additionally, monophosphorylated inhibitors were synthesised to determine the relative importance of the two phosphate groups of this bisphosphate analogue for enzyme inhibition. The removal of either of these two phosphate groups gave less potent inhibitors for both enzymes.
Biomolecular Interaction Centre and Department of Chemistry, University of Canterbury, Christchurch 8040, New Zealand.
Aidan N
AN
Harrison
Sebastian
S
Reichau
Emily J
EJ
Parker
D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011756:Diphosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018716:Molecular Mimicry; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011756:Diphosphates; D004791:Enzyme Inhibitors; C020011:2-dehydro-3-deoxyphosphooctonate aldolase; D000446:Aldehyde-Lyases