Swainsonine biosynthesis

Various glycosidases are involved in the modification, biosynthetic processing and trafficking of glycoproteins. Gastanospermin and swainsonine, plant inhibitors of such glycosidases, interfere with glycoprotein biosynthesis and are consequently very toxic (Table 13.1). 

Tulsiani DRP, Harris TM, Touster O. Swainsonine inhibits the biosynthesis of complex glycoproteins by inhibition of Golgi mannosidase-11. J. Biol. Chem. 1982 257(14) 7936-7939. 

The biosynthesis of swainsonine was studied in the fungus Rhizoctonia leguminicola The piperidine ring was shown to be derived from lysine via pipecolic acid. A noteworthy... 

Harris et al. postulated that (liS, 8aS)-( + )-l-hydroxyindolizidine (109) and (lf ,8aS)-l-hydroxyindolizidine (110) were pivotal intermediates in the biosynthesis of slafi-amine (3) and swainsonine (cf. Section lU.C) in the fungus Rhizoctonia leguminicola (74). Compound 110 was subsequently isolated as e acetate from extracts of the diablo locoweed. Astragalus oxyphysus (75). 

The absolute configuration of (-)-swainsonine (1) was deduced on the basis of its biosynthesis and unambiguous nuclear magnetic resonance assignments.The relative stereochemistry of swainsonine was determined by X-ray crystallography. Noncarbohydrates have been used for the total synthesis of swainsonine and its isomers.The first total synthesis of 1 has established its absolute stereochemistry as (15, 2i ,8i ,8ai )-... 

The discovery of the indolizidine alkaloid swainsonine (35) and its A-oxide (37) in the leguminous gtn tdi Astragalus, Oxytropis, and Swainsona suggests a biosynthetic route somewhat resembling those of pyrrolizidine and quinolizidine alkaloid biosynthesis (Harris et al, 1987 Kinghom and Balandrin, 1984). The similarity of certain indolizidine alkaloids to coniine-related compounds, such as 8-coniceine (not naturally occurring) has been observed. 

The biosynthesis of slaframine (38) and swainsonine (35) in Rhizoctonia leguminicola involves lysine and proceeds via the intermediacy of pipecolic acid. Carbon atoms 2 and 3 have been demonstrated to come from acetate via malonate (Fig. 30.14). The biosynthesis of swainsonine and related compounds in plants does not appear to have been investigated (Elbein and Molyneux, 1987 Harris et al, 1987 Howard and Michael, 1986). 

Fig. 30.14. Biosynthesis of slaframine and swainsonine in Rhizoctonia leguminocola (modified from Howard and Michael, 1986 used with permission of the copyright owner, Academic Press, Orlando, FL),...

Animal systems contain three distinct types of a-mannos-idases. Swainsonine (35) inhibits one of these completely at concentrations as low as 20 jxm. At much higher levels (more than 50 times), this compound did not exhibit inhibitory activity toward 3-mannosidase, a- or p-glucosidase, a- or p-galactosidase, p-N-acetylhexosaminidase, or a-L-fiicosidase (Elbein and Molyneux, 1987). The alkaloid also alters normal processing of A -linked oligosaccharides and biosynthesis of glycoproteins. 

Harris CM, Schneider MJ, Ungemach FS, HiU JE, Harris TM (1998) Biosynthesis of the toxic alkaloids slaframine and swainsonine in Rhizoctonia leguminicola Metabolism of 1-hydroxy-indolizidines. J Am Chem Soc 110 940-949... 

Both (lS,8aS)-(- -)-indohzidin-l-ol (88) and (lR,8a -(—)-indohzidin-l-ol (89) are intermediates in the biosynthesis of slaframine (9) and swainsonine (c Section 3.5) in the fungus Rhizoctonia legutninicolaf The former has also been isolated as the acetate from the diablo locoweed. Astragalus oxyphysus7 A related compound, 8-methylindolizidin-l-ol (90), has been claimed as a new toxic principle in extracts of Oxytropis kansuensis but details are sketchy (Figure 6). AH recent publications in this area have dealt with the synthesis of 88, 89, and the enantiomer of 89. 

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