Naturally Occurring Sulfonium-Ion Glucosidase Inhibitors and Their Derivatives: A Promising Class of Potential Antidiabetic Agents

Abstract

In humans, four different enzymes mediate the digestion of ingested carbohydrates. First salivary and pancreatic α-amylases, the two endoacting retaining glucosidases, break down the complex starch molecules into smaller linear maltose-oligomers (LM) and branched α-limit dextrins (αLDx). Then two retaining exoglucosidases, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI), convert those molecules into glucose in the small intestine. The small intestinal brush-border epithelial cells anchor MGAM and SI, and each contains a catalytic N- and C-terminal subunit, ntMGAM, ctMGAM, ntSI, and ctSI, respectively. All four catalytic domains have, to varying extents, α-1,4-exohydrolytic glucosidase activity and belong to the glycoside hydrolase family 31 (GH31). ntSI and ctSI show additional activity toward α-1,6 (isomaltose substrates) and α-1,2 (sucrose) glycosidic linkages, respectively. Because they mediate the final steps of starch digestion, both MGAM and SI are important target enzymes for the treatment of type-2 diabetes. Because of their potent inhibitory activities against the mammalian intestinal α-glucosidases, sulfonium-ion glucosidase inhibitors isolated from the antidiabetic herbal extracts of various Salacia species have received considerable attention recently. Thus far, researchers have isolated eight sulfonium-ion glucosidase inhibitors from Salacia species: salaprinol, salacinol, ponkoranol, kotalanol, and four of their corresponding de-O-sulfonated compounds, the structures of which comprise a 1,4-anhydro-4-thio-d-arabinitol and a polyhydroxylated acyclic side chain. Some of these compounds more strongly inhibit human intestinal α-glucosidases than the currently available antidiabetic drugs, acarbose and miglitol, and could serve as lead candidates in the treatment of type-2 diabetes. In this Account, we summarize progress in the field since 2010 with this class of inhibitors, with particular focus on their selective inhibitory activities against the intestinal glucosidases. Through structure-activity relationship (SAR) studies, we have modified the natural compounds to derive more potent, nanomolar inhibitors of human MGAM and SI. This structural optimization also yielded the most potent inhibitors known to date for each subunit. Furthermore, we observed that some of our synthetic inhibitors selectively blocked the activity of some mucosal α-glucosidases. Those results led to our current working hypothesis that selective inhibitors can dampen the action of a fast digesting subunit or subunits which places the burden of digestion on slower digesting subunits. That strategy can control the rate of starch digestion and glucose release to the body. Decreasing the initial glucose spike after a carbohydrate-rich meal and extending postprandial blood glucose delivery to the body can be desirable for diabetics and patients with other metabolic syndrome-associated diseases.

Molecular characterization and heterologous expression of a Xanthophyllomyces dendrorhous α-glucosidase with potential for prebiotics production

“…strain H11 (Shen et al 2014) are included in this family. By contrast, family GH31 includes important enzymes such as the human lysosomal α-glucosidase (whose deficiency results in the Pompe's disease; Hermans et al 1991;Raben et al 2002) or the sucrose-isomaltase (target of inhibition of some anti-diabetes drugs; Mohan et al 2014), much less data concerning this protein family has been clarified.…”

Eurothiocin A and B, Sulfur-Containing Benzofurans from a Soft Coral-Derived Fungus Eurotium rubrum SH-823

“…In the course of this study, a soft coral-derived fungus, Eurotium rubrum SH-823, attracted our attention because the EtOAc extract of the fungal fermentation on rice exhibited significant α-glucosidase inhibitory activity. α-glucosidase is an important target enzyme for the treatment of type-2 diabetes, which is a metabolic disorder characterized by elevated blood glucose [28,29]. Such reversible inhibitors, including acarbose and voglibose, are currently used clinically to control blood glucose levels of patients.…”

Glomerular Transcriptome Profiles in Focal Glomerulosclerosis: New Genes and Pathways for Steroid Resistance

“…MGAM encodes maltase-glucoamylase, which is an intestinal brush border membrane enzyme involved in carbohydrate digestion [20]. MGAM expresses in the kidney, an important target enzyme for the treatment of type-2 diabetes and also takes part in energy supply [21]. PRLR, with prolactin as ligands, prolactin/PRLR signaling is crucial in keeping water and electrolyte balance, which is critical for osmo- regulation of human kidney [22].…”