NUTRIENT - GENE INTERACTIONS
Location: Children Nutrition Research Center (Houston, Tx)
Title: INHIBITION OF RECOMBINANT HUMAN MALTASE GLUCOAMYLASE BY SALACINOL AND DERIVATIVES
| Rossi, Elena - UNIV TORONTO, CANADA |
| Sim, Lyann - ONTARIO CANCER INST |
| Kuntz, Douglas - ONTARIO CANCER INST |
| Hahn, Dagmar - UNIV BERNE, SWITZERLAND |
| Johnston, Blair - SIMON FRASER UNIV, CANADA |
| Ghavami, Ahmad - SIMON FRASER UNIV, CANADA |
| Szczepina, Monica - SIMON FRASER UNIV, CANADA |
| Kumar, Nag - SIMON FRASER UNIV, CANADA |
| Sterchi, Erwin - UNIV BERNE, SWITZERLAND |
| Nichols, Buford - BAYLOR COLLEGE MED |
| Pinto, B - SIMON FRASER UNIV, CANADA |
| Rose, David - UNIV TORONTO, CANADA |
Submitted to: FEBS Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 13, 2006
Publication Date: June 1, 2006
Citation: Rossi, E.J., Sim, L., Kuntz, D.A., Hahn, D., Johnston, B.D., Ghavami, A., Szczepina, M.G., Kumar, N.S., Sterchi, E.E., Nichols, B.L., Pinto, B.M., Rose, D.R. 2006. Inhibition of recombinant human maltase glucoamylase by salacinol and derivatives. FEBS Journal. 273:2673-2683.
Interpretive Summary: Inhibitors targeting pancreatic alpha-amylase and intestinal alpha-glucosidases slow glucose digestion from food starches and are used in treatment of Type II diabetes. Maltase-glucoamylase (MGA) is a human alpha-glucosidase on the surface of intestinal cells and is responsible for the rate of starch digestion to glucose. This paper reports production and purification of human recombinant MGA amino terminal catalytic domain (MGAnt). Inhibition of MGAnt activity was tested with salacinol, a naturally occurring alpha-glucosidase inhibitor, and acarbose, a current antidiabetic agent. These results provide information on mechanisms of inhibition of MGAnt that will guide development of new antidiabetic treatments.
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.