| dc.description.abstract | Sucrase isomaltase (SI) and maltase glucoamylase (MGAM) are both large Family 31 glycoside hydrolases with α-glucogenic activity (Cantarel et al., 2009; Lombard et al., 2014). Mammalian SI and MGAM, expressed predominantly in the small intestine, play essential roles in the process of starch digestion. Because their activities directly control the rate of α-glucogenesis in the small intestine, they also pose a useful target for the design of α-glucosidase inhibitors, a class of drugs useful for the treatment of type 2 diabetes and other metabolic disorders.
The purpose of this work was to characterize inhibition kinetics for enantiomeric pyrrolidine iminosugars 1,4-dideoxy-1,4-imino-L-arabinatol (LAB-1) and 1,4-dideoxy-1,4-imino-D-arabinatol (DAB-1) with N- and C-terminal catalytic subunits of SI and MGAM, as well as for an additional C-terminal MGAM isoform, in the presence of three different substrates. Kinetic analysis indicates that LAB-1 is a more potent inhibitor of maltose and PNP-glucose hydrolysis than is DAB-1. Both mixed and competitive inhibition kinetics are observed for varying combinations of inhibitor, enzyme, and substrate. A general hypothesis regarding the binding of each of the two inhibitors is presented. Additionally, evidence for substrate inhibition of palatinose hydrolysis for Nt-SI and Nt-MGAM is reported and discussed. | en |
