title: Inhibition of recombinant human maltase glucoamylase by salacinol and derivatives.
abstract: Inhibitors targeting pancreatic alpha-amylase and intestinal alpha-glucosidases delay glucose production following digestion and are currently used in the treatment of Type II diabetes. Maltase-glucoamylase (MGA), a family 31 glycoside hydrolase, is an alpha-glucosidase anchored in the membrane of small intestinal epithelial cells responsible for the final step of mammalian starch digestion leading to the release of glucose. This paper reports the production and purification of active human recombinant MGA amino terminal catalytic domain (MGAnt) from two different eukaryotic cell culture systems. MGAnt overexpressed in Drosophila cells was of quality and quantity suitable for kinetic and inhibition studies as well as future structural studies. Inhibition of MGAnt was tested with a group of prospective alpha-glucosidase inhibitors modeled after salacinol, a naturally occurring alpha-glucosidase inhibitor, and acarbose, a currently prescribed antidiabetic agent. Four synthetic inhibitors that bind and inhibit MGAnt activity better than acarbose, and at comparable levels to salacinol, were found. The inhibitors are derivatives of salacinol that contain either a selenium atom in place of sulfur in the five-membered ring, or a longer polyhydroxylated, sulfated chain than salacinol. Six-membered ring derivatives of salacinol and compounds modeled after miglitol were much less effective as MGAnt inhibitors. These results provide information on the inhibitory profile of MGAnt that will guide the development of new compounds having antidiabetic activity.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Canada.
authors.forename: Elena J
authors.initials: EJ
authors.lastname: Rossi
authors.forename: Lyann
authors.initials: L
authors.lastname: Sim
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Kuntz
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hahn
authors.forename: Blair D
authors.initials: BD
authors.lastname: Johnston
authors.forename: Ahmad
authors.initials: A
authors.lastname: Ghavami
authors.forename: Monica G
authors.initials: MG
authors.lastname: Szczepina
authors.forename: Nag S
authors.initials: NS
authors.lastname: Kumar
authors.forename: Erwin E
authors.initials: EE
authors.lastname: Sterchi
authors.forename: Buford L
authors.initials: BL
authors.lastname: Nichols
authors.forename: B M
authors.initials: BM
authors.lastname: Pinto
authors.forename: David R
authors.initials: DR
authors.lastname: Rose
mesh_terms: D020909:Acarbose / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013431:Sulfates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014162:Transfection; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D011994:Recombinant Proteins; D013402:Sugar Alcohols; D013431:Sulfates; C427963:salacinol; D000520:alpha-Glucosidases; D020909:Acarbose