Castanospermine glycosidase inhibition

A case similar to the slow, practically irreversible inhibition of jack bean a-D-mannosidase by swainsonine is represented by the interaction of castanospermine with isomaltase and rat-intestinal sucrase. Whereas the association constants for the formation of the enzyme-inhibitor complex were similar to those of other slow-binding glycosidase inhibitors (6.5 10 and 0.3 10 M s for sucrase and isomaltase, respectively), the dissociation constant of the enzyme-inhibitor complex was extremely low (3.6 10 s for sucrase) or could not be measured at all (isomaltase), resulting in a virtually irreversible inhibition. Danzin and Ehrhard discussed the strong binding of castanospermine in terms of the similarity of the protonated inhibitor to a D-glucosyl oxocarbenium ion transition-state, but were unable to give an explanation for the extremely slow dissociation of the enzyme-inhibitor complex. 

Winchester BG Cenci di Bello I, Richardson AC, Nash, RJ, Fellows LE, Ramsden NG Fleet G. (1990) The structural basis of the inhibition of human glycosidases by castanospermine analogues. Biochem J 269 227-231. 

Both alkaloids (castanospermine and swansonine) have the ability to inhibit glycosidase enzymes (GEs), the activity of which is necessary in glycoprotein biosynthesis. 

Indolizidine alkaloids [15] such as castanospermine and swainsonine are formed from pipecolic acid, an amino acid derived from lysine, which can be elongated by malonyl-CoA followed by ring closure. When protonated, these alkaloids are oxonium mimics strongly inhibiting glycosidases. 

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