The effects of castanospermine and swainsonine on the activity and synthesis of intestinal sucrase.
Castanospermine is an indolizidine alkaloid that is found in the seeds of the Australian tree Castanospermum australe. These seeds have been reported to be toxic to animals and to cause severe gastrointestinal upset. In order to determine whether castanospermine is responsible for this toxicity, the alkaloid was injected into young mice or rats, and its effects on various intestinal disaccharidases were determined. Another indolizidine alkaloid, the alpha-mannosidase inhibitor swainsonine, was also tested to compare its effects to those of castanospermine. Castanospermine strongly and rapidly inhibited the activity of the disaccharidases, sucrase, maltase, and trehalase, with sucrase being the most sensitive to inhibition. The loss of activity of these enzymes, especially sucrase, in injected animals appeared to be due to a direct inhibition of enzyme activity, rather than to a change in the structure of the glycan chains of the enzyme, since only minor alterations in carbohydrates were observed. On the other hand, swainsonine, when injected into animals, also profoundly decreased the activity of the sucrase, but this alkaloid had no direct effect on sucrase activity although it did markedly alter the carbohydrate nature of this glycoprotein. This change in oligosaccharide structure may affect protein conformation, stability, or targeting, any or all of which may in turn affect activity. In in vitro studies with the purified enzyme, castanospermine was found to be a competitive inhibitor of intestinal sucrase, but it was a noncompetitive inhibitor of intestinal maltase. A number of other glucosidase inhibitors that inhibit sucrase activity in vitro are also described.
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Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205.
Ghidoni
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J
Elbein
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D000818:Animals; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007212:Indolizines / Q000494:pharmacology*; D007422:Intestines / Q000201:enzymology*; D007700:Kinetics; D008871:Microvilli / Q000201:enzymology; D009844:Oligosaccharides / Q000737:chemistry; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D013393:Sucrase / Q000737:chemistry / Q000378:metabolism*; D017026:Swainsonine / Q000494:pharmacology*; D013997:Time Factors; D000520:alpha-Glucosidases / Q000378:metabolism; D054836:Indolizidines
D006023:Glycoproteins; D006026:Glycoside Hydrolases; D007212:Indolizines; D009844:Oligosaccharides; D013393:Sucrase; D017026:Swainsonine; D000520:alpha-Glucosidases; C037806:castanospermine; D054836:Indolizidines