validamine and valiolamine

Three pseudo-aminosugars, validamine, valienamine and valiolamine, produced by Streptomyces hygroscopicus subsp. limoneus showed potent inhibitory action on rat small intestinal carbohydrase activities such as sucrase, maltase, glucoamylase, isomaltase and trehalase activities, but negligible action on lactase activity and pancreatic alpha-amylase activity. Where inhibition was seen, kinetic analysis showed fully competitive inhibition of the carbohydrase activities by all three inhibitors. Valiolamine has more potent carbohydrase inhibitory activity than validamine or valienamine, and the apparent Ki values of valiolamine for sucrase, maltase, glucoamylase, isomaltase and trehalase activities were 3.2 x 10(-7), 2.9 x 10(-6), 1.2 x 10(-6), 9.1 x 10(-7) and 4.9 x 10(-5) M, respectively, which are 10(-5) to 10(-3) times smaller than the apparent Km values.

Topics: Animals; Cyclohexenes; Glycoside Hydrolases; Hexosamines; In Vitro Techniques; Inositol; Intestine, Small; Male; Microvilli; Rats; Rats, Inbred Strains

We examined the inhibitory effect of three pseudo-aminosugars (validamine, valienamine, and valiolamine), which were isolated from the broth of Streptomyces hygroscopicus, on the oligosaccharide-processing glucosidases I and II involved in glycoprotein biosynthesis in rat liver. Both glucosidases I and II were inhibited to the same extent by the pseudoaminosugars, and valiolamine had a more potent inhibitory activity than validamine or valienamine. A 50% inhibition of valiolamine was observed at 12 microM for glucosidase I and glucosidase II activities acting respectively on the substrates Glc3Man9GlcNAc2 and p-nitrophenyl alpha-D-glucopyranoside. Further, in order to investigate further the ability of valiolamine to inhibit glucosidase I, reaction products were analyzed by gel filtration on a Bio-Gel P-4 column. We also compared the inhibitory action of these pseudo-aminosugars on the acid alpha-glucosidase of rat liver lysosomes. They competitively inhibited the hydrolysis of both substrates, maltose and glycogen. Valiolamine again had a more potent lysosomal alpha-glucosidase inhibitory activity than the other two. The Ki values of valiolamine for the hydrolysis of maltose and glycogen were 8.1 and 11 microM, respectively. Valiolamine is a particularly effective inhibitor of oligosaccharide glucosidases I and II and of lysosomal alpha-glucosidase. Hence valiolamine might be useful as a research tool in investigations of carbohydrate metabolism.

Topics: alpha-Glucosidases; Amino Sugars; Animals; Chromatography, Gel; Cyclohexenes; Glucosidases; Glycoside Hydrolase Inhibitors; Hexosamines; In Vitro Techniques; Inositol; Kinetics; Liver; Lysosomes; Male; Rats; Rats, Inbred Strains; Streptomyces

Various kinds of N-substituted valiolamine derivatives, including compounds 23a, 24a, and 34a, which are structurally analogous to the key pseudodisaccharides (25a and 26a) of naturally occurring oligosaccharide alpha-D-glucosidase inhibitors, have been synthesized and estimated by the measure of inhibitory activity against porcine sucrase and maltase. The N-substituted valiolamine derivatives evaluated in this study have been found to be more potent than the corresponding N-substituted valienamine derivatives as well as the parent valiolamine. It is noteworthy that even simple N-substituted valiolamine derivatives such as N-[2-hydroxy-1-(hydroxymethyl)ethyl]-, N-[(1R,2R)-2-hydroxycyclohexyl]-, and N-[(R)-(-)-beta-hydroxyphenethyl]valiolamine (6, 8a, and 9a) have the stronger alpha-D-glucosidase inhibitory activity against porcine intestinal maltase and sucrase than naturally occurring oligosaccharide alpha-D-glucosidase inhibitors.

Topics: Animals; Cyclohexanols; Glucosidases; Glycoside Hydrolase Inhibitors; Hypoglycemic Agents; Inositol; Stereoisomerism; Structure-Activity Relationship; Swine