Mannosidase swainsonine

Another therapeutic application of polyhydroxylated alkaloids is as anti-viral agents. Inhibitors of processing a-glucosidases, such as castanospermine and DNJ, have been shown to decrease the infectivity of human immunodeficiency virus (HIV) in vitro at concentrations which are not cytotoxic to lymphocytes, whereas specific inhibitors of processing a-mannosidases (swainsonine and 1-deoxymannojirimycin) have no effect on Castanospermine and DNJ also reduce the infectivity of other retroviruses... 

Inhibition of D-Mannosidases and D-Glucosidases by Swainsonine and Castanospermine, Respectively... 

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. 

Colgate, S. M., Dorling, P. R. and Huxtable, C. R. 1979. A spectroscopic investigation of swainsonine an a-mannosidase inhibitor isolated from Swainsona canescens. Austral. J. Chem. 32 2257-2264. 

Swainsonine (1) is of great biochemical interest since it is a potent and specific inhibitor of both lysosomal a-mannosidase and mannosidase II, which are involved in the cellular degradation of polysaccharides and in the processing of asparagine-linked glycoproteins, respectively [1]. 

Figure 2.13 The indolizidine alkaloid toxin swainsonine (a potent inhibitor of a-mannosidase), responsible for locoweed toxicosis.

Cenci di Bello I, Fleet G Namgoong SK, Tadano K-I, Winchester B. (1989) Structure-activity relationship of swainsonine. Inhibition of human alpha-mannosidases by swainsonine analogues. BiochemJ 259 855-861. 

R)-5-C-(4-t-Butyl)benzoylmethyl swainsonine Bt2199 Bacteroides thetaiotaomicron (GH 92) a-Mannosidase II, 3EJP, 293... 

One particular example of the early extraction of a chemical from a plant, a small tree found in the rainforests of eastern Queensland, would be that of acronycine 1 [1,2], an alkaloid currently undergoing clinical trials as an anticancer agent. More recently, a group in Perth at Murdoch University succeeded in extracting the alkaloid, swainsonine 2 from a desert shrub which causes poisoning in cattle [3]. Swainsonine has been found to exhibit an interesting spectrum of biological activity [4], especially as a potent, reversible inhibitor of various a-D-mannosidases [5]. 

A trail pheromone of the Pharaoh ant was identified as 3-butyl-5-methylindolizidine of the stereochemistry given in (219) (75JHC289). Slaframine (220) is a metabolite isolated from Rhizoctonia leguminicola responsible for producing excessive salivation in cattle. A stereoselective synthesis was reported (73JOC3848). Swainsonine (221), a potent inhibitor of a-mannosidase, has been isolated from Swainsona caneszens. The stereochemistry was derived from the NMR spectrum (79AJC2257). 

Inhibitors can block the pathway at specific steps, causing the accumulation of biosynthetic intermediates. Castanospermine inhibits the a-glucosidase that removes the first glucose deoxymannojirimycin inhibits the a-mannosidase I that removes mannose from the Man8 intermediate, and swainsonine blocks the a-mannosidase II that removes mannose from the Man5 intermediate. In the presence of swainsonine, hybrid N-linked carbohydrates are synthesized. 

Since mannosido.se results from a genetically derrved absence of lysosomal a-mannosidase that leads to an accumulation of mannose-rich oligosaccharides, the effects of swainsonine (1) on this enzyme were investigated. The alkaloid, which bears a structural resemblance to the open-chain form of D-man nose (2), was in fact shown to be a reversible inhibitor of lysosomal a-mannosidase.8... 

A detailed spectroscopic study has shown that swainsonine, from Swainsona canescens (Benth.) A. Lee, is 8a/3-indolizidine-la,2a,8 3-triol (1), and the structure and relative configuration have been confirmed by X-ray crystallography.1 Swainsonine is a potent inhibitor of a-mannosidase, and in animals it produces an accumulation of mannose-rich oligosaccharides in the lysosomal system of cells, leading to organ dysfunction and clinical disease.1... 

Another mode of interference would be the inhibition of carriers for amino acids, sugars, or lipids, or of digestive enzymes. Relevant alkaloids are the polyhydroxyalkaloids, such as swainsonine, deoxynoijirimycin, and castanospermine, that inhibit hydrolytic enzymes, such as glucosi-dase, galactosidase, trehalase (trehalose is a sugar in insects which is hydrolyzed by trehalase), and mannosidase selectively (Table IV). 

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