ABSTRACT
Several 5-O-alkyl- and 5-C-alkyl-mannitol bis-phosphates were synthesized and comparatively assayed as inhibitors of fructose bis-phosphate aldolases (Fbas) from rabbit muscle (taken as surrogate model of the human enzyme) and from Trypanosoma brucei. A limited selectivity was found in several instances. Crystallographic studies confirm that the 5-O-methyl derivative binds competitively with substrate and the 5-O-methyl moiety penetrating deeper into a shallow hydrophobic pocket at the active site. This observation can lead to the preparation of selective competitive or irreversible inhibitors of the parasite Fba.
ABSTRACT
We report the first unambiguous syntheses of glucitol-1,6-bis-phosphate and mannitol-1,6-bis-phosphate and their competitive inhibition of various fructose bis-phosphate aldolases.
Subject(s)
Fructose-Bisphosphate Aldolase/antagonists & inhibitors , Mannitol Phosphates/chemical synthesis , Sorbitol/analogs & derivatives , Sorbitol/chemical synthesis , Sugar Phosphates/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Helicobacter pylori/enzymology , Mannitol Phosphates/pharmacology , Molecular Structure , Saccharomyces cerevisiae/enzymology , Sorbitol/pharmacology , Sugar Phosphates/pharmacologyABSTRACT
We report the synthesis and biochemical evaluation of new competitive inhibitors of the cytosolic (NADH-dependent) glycerophosphate dehydrogenase. The best tested compound, phosphono-propionohydroxamic acid, with a Ki of 6 microM, might be of interest as an anti-obesity drug.
Subject(s)
Cytosol/enzymology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycerolphosphate Dehydrogenase/antagonists & inhibitors , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Muscle, Skeletal/enzymology , NAD/metabolism , Animals , Cytosol/drug effects , Humans , Hydrogen Bonding , Kinetics , Magnetic Resonance Spectroscopy , Molecular Conformation , Muscle, Skeletal/drug effects , Rabbits , Spectrometry, Mass, Electrospray IonizationABSTRACT
D-glucosaminic acid (2-amino-2-deoxy-D-gluconic acid), a component of bacterial lipopolysaccharides and a chiral synthon, is easily prepared on a multigram scale by air oxidation of D-glucosamine (2-amino-2-deoxy-D-glucose) catalysed by glucose oxidase.
Subject(s)
Glucosamine/analogs & derivatives , Glucosamine/biosynthesis , Glucosamine/metabolism , Aspergillus niger/enzymology , Catalase/metabolism , Glucosamine/chemistry , Glucose Oxidase/metabolism , Hydrogen-Ion Concentration , Molecular Structure , Oxidation-ReductionABSTRACT
The O-chain polysaccharide (O-PS) of Bordetella avium was isolated from the lipopolysaccharide by mild acid hydrolysis to remove the lipid A, followed by hydrofluorolysis to remove the lipopolysaccharide core oligosaccharide leaving a residual O-PS for structural analysis. High resolution (1)H and (13)C NMR and MALDI studies showed the O-chain to be a polymer composed of 1,4-linked 2-acetamidino-3-[3-hydroxybutanamido]-2,3-dideoxy-beta-D-glucopyranosyluronic acid residues.
