title: New glucosidase inhibitors from an ayurvedic herbal treatment for type 2 diabetes: structures and inhibition of human intestinal maltase-glucoamylase with compounds from Salacia reticulata.
abstract: An approach to controlling blood glucose levels in individuals with type 2 diabetes is to target alpha-amylases and intestinal glucosidases using alpha-glucosidase inhibitors acarbose and miglitol. One of the intestinal glucosidases targeted is the N-terminal catalytic domain of maltase-glucoamylase (ntMGAM), one of the four intestinal glycoside hydrolase 31 enzyme activities responsible for the hydrolysis of terminal starch products into glucose. Here we present the X-ray crystallographic studies of ntMGAM in complex with a new class of alpha-glucosidase inhibitors derived from natural extracts of Salacia reticulata, a plant used traditionally in Ayuverdic medicine for the treatment of type 2 diabetes. Included in these extracts are the active compounds salacinol, kotalanol, and de-O-sulfonated kotalanol. This study reveals that de-O-sulfonated kotalanol is the most potent ntMGAM inhibitor reported to date (K(i) = 0.03 microM), some 2000-fold better than the compounds currently used in the clinic, and highlights the potential of the salacinol class of inhibitors as future drug candidates.
authors.affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7 Canada.
authors.forename: Lyann
authors.initials: L
authors.lastname: Sim
authors.forename: Kumarasamy
authors.initials: K
authors.lastname: Jayakanthan
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Nasi
authors.forename: Blair D
authors.initials: BD
authors.lastname: Johnston
authors.forename: B Mario
authors.initials: BM
authors.lastname: Pinto
authors.forename: David R
authors.initials: DR
authors.lastname: Rose
mesh_terms: D020909:Acarbose / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008515:Medicine, Ayurvedic; D010936:Plant Extracts / Q000737:chemistry; D049918:Salacia / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000737:chemistry; D013431:Sulfates / Q000737:chemistry; D000520:alpha-Glucosidases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D010936:Plant Extracts; D013402:Sugar Alcohols; D013431:Sulfates; C427963:salacinol; D000520:alpha-Glucosidases; D020909:Acarbose