Selection of a high-energy bioactive conformation of a sulfonium-ion glycosidase inhibitor by the enzyme glucoamylase G2.
Transferred nuclear Overhauser effect and rotating-frame Overhauser enhancement NMR spectroscopies are used to probe the conformation of a bicyclic sulfonium ion, which is an analogue of the naturally occurring glycosidase inhibitor castanospermine, bound to the enzyme glucoamylase G2. Enzyme inhibition assays indicate that the bicyclic sulfonium ion is a slightly better inhibitor (K(i) = 1.32 mM) of glucoamylase G2 than the naturally occurring sulfonium-ion glycosidase inhibitor, salacinol, with a K(i) value of 1.7 mM. The NMR results are interpreted in terms of the selection by the enzyme of a high-energy conformation of the ligand that is already represented in the ensemble of free-ligand conformations.
Department of Chemistry, Simon Fraser University, Burnaby, B.C., Canada, V5A 1S6.
Margaret A
MA
Johnson
Morten T
MT
Jensen
Birte
B
Svensson
B Mario
BM
Pinto
D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology; D002240:Carbohydrate Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005087:Glucan 1,4-alpha-Glucosidase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D007212:Indolizines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011487:Protein Conformation; D013452:Sulfonium Compounds / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics; D054836:Indolizidines
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005087:Glucan 1,4-alpha-Glucosidase; D007212:Indolizines; D013452:Sulfonium Compounds; C037806:castanospermine; D054836:Indolizidines