Castanospermine Explained

Castanospermine is an indolizidine alkaloid first isolated from the seeds of Castanospermum australe.^[1] It is a potent inhibitor of some glucosidase enzymes^[2] and has antiviral activity in vitro and in mouse models.^[3]

The castanospermine derivative celgosivir is an antiviral drug candidate currently in development for possible use in treating hepatitis C virus (HCV) infection.^[4]

Biosynthesis

L-Lysine undergoes a transamination to form α-aminoadipic acid. α-Aminoadipic acid undergoes a ring closure and then a reduction to form L-pipecolic acid.^{[5] [6] [7]}

In the alternate pathway L-Lys cyclizes and forms the enamine, which reduces to L-pipecolic acid.

HSCoA and then malonyl-CoA react in a Claisen reaction with L-pipecolic acid to form SCoA ester which undergoes a ring closure to form 1-indolizidinone. The carbonyl on 1-indolizidinone is reduced to the hydroxyl group. The molecule is then further hydroxylated to form the final product castanospermine.^[8]

See also

• Swainsonine

Notes and References

1. Hohenschutz, Liza D. . Bell, E. Arthur . Jewess, Phillip J. . Leworthy, David P. . Pryce, Robert J. . Arnold, Edward . Clardy, Jon . Jon Clardy . Castanospermine, a 1,6,7,8-tetrahydroxyoctahydroindolizine alkaloid, from seeds of Castanospermum australe . Phytochemistry . 1981 . 20 . 4 . 811–14 . 10.1016/0031-9422(81)85181-3. 1981PChem..20..811H .
2. PNAS . 1985 . 82 . 1 . 93–97 . Castanospermine inhibits alpha-glucosidase activities and alters glycogen distribution in animals . R Saul . J J Ghidoni . R J Molyneux . A D Elbein . amp . 10.1073/pnas.82.1.93 . 3881759 . 396977 . 1985PNAS...82...93S . free .
3. Whitby K, Pierson TC, Geiss B, Lane K, Engle M, Zhou Y, Doms RW, Diamond MS . Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo . J Virol . 2005 . 79 . 14 . 8698–706 . 10.1128/JVI.79.14.8698-8706.2005 . 15994763 . 1168722.
4. 19649930. 2009. Durantel. D.. Celgosivir, an alpha-glucosidase I inhibitor for the potential treatment of HCV infection. Current Opinion in Investigational Drugs. 10. 8. 860–70.
5. Hartmann. Michael. Kim. Denis. Bernsdorff. Friederike. Ajami-Rashidi. Ziba. Scholten. Nicola. Schreiber. Stefan. Zeier. Tatyana. Schuck. Stefan. Reichel-Deland. Vanessa. 2017-03-22. Biochemical Principles and Functional Aspects of Pipecolic Acid Biosynthesis in Plant Immunity. Plant Physiology. 174. 1. 124–153. 10.1104/pp.17.00222. 28330936. 5411157. 0032-0889.
6. Hartman. Michael. Summer 2018. Biochemical Principles and Functional Aspects of Pipecolic Acid Biosynthesis in Plant Immunity. Plant Physiology. 174. 1. 124–153. 10.1104/pp.17.00222. 28330936. 5411157.
7. Book: Walsh, Christopher. Natural Product Biosynthesis: Chemical Logic and Enzymatic Machinery. Royal Society of Chemistry. 2017. 978-1788010764. 270.
8. Book: Dewick, Paul. Medicinal Natural Products A Biosynthetic Approach. Wiley. 2009. 978-0-470-74167-2. United Kingdom. 330.