Swainsonine Explained

Swainsonine is an indolizidine alkaloid. It is a potent inhibitor of Golgi alpha-mannosidase II, an immunomodulator, and a potential chemotherapy drug.[1] As a toxin in locoweed (likely its primary toxin[2]) it also is a significant cause of economic losses in livestock industries, particularly in North America. It was first isolated from Swainsona canescens.[3]

Pharmacology

Swainsonine inhibits glycoside hydrolases, specifically those involved in N-linked glycosylation. Disruption of Golgi alpha-mannosidase II with swainsonine induces hybrid-type glycans. These glycans have a Man5GlcNAc2 core with processing on the 3-arm that resembles so-called complex-type glycans.

The pharmacological properties of this product have not been fully investigated.

Sources

Some plants, such as Oxytropis ochrocephala, do not produce the toxic compound themselves, but are host to endophytic fungi which produces swainsonine, such as Alternaria oxytropis. [4]

Fungal Sources
Family Fungi
Pleosporaceae Undifilum oxytropis[5]
Clavicipitaceae Metarhizium anisopliae[6]
Plant sources
Family Plants
Fabaceae Swainsona canescens, Astragalus earlei, A. mollissimus, A. pubentissimus, A. lentiginosis, A. wootoni, A. nothoxys, A. tephrodes, A. humistratus[7] [8]
Convolvulaceae Jacquemontia corymbulosa, Ipomoea verbascoidea, I. subincana, I. megapotamica, I. rosea, I. carnea, I. sericophylla, I. riedelii[9] [10] [11] [12]

Biosynthesis

The biosynthesis of swainsonine has been investigated in the fungus Rhizoctonia leguminicola, and it initially involves the conversion of lysine into pipecolic acid. The pyrrolidine ring is then formed via retention of the carbon atom of the pipecolate's carboxyl group, as well as the coupling of two more carbon atoms from either acetate or malonate to form a pipecolylacetate. The retention of the carboxyl carbon is striking, since it is normally lost in the biosynthesis of most other alkaloids.[13]

The resulting oxoindolizidine is then reduced to (1R,8aS)- 1-hydroxyindolizidine, which is subsequently hydroxylated at the C2 carbon atom to yield 1,2-dihydroxyindolizidine. Finally, an 8-hydroxyl group is introduced through epimerization at C-8a to yield swainsonine. Schneider et al. have suggested that oxidation occurs at C-8a to give an iminium ion. Reduction from the β face would then yield the R configuration of swainsonine, as opposed to the S configuration of slaframine, another indolizidine alkaloid whose biosynthesis is similar to that of swainsonine during the first half of the pathway and also shown above alongside that of swainsonine. The instance at which oxidation and reduction occur with regard to the introduction of the hydroxyl groups at the C2 and C8 positions is still under investigation.[13]

The biosynthetic pathway of swainsonine has also been investigated in the Diablo locoweed (Astragalus oxyphysus). Through detection of (1,8a-trans)-1-hydroxyindolizidine and (1,8a-trans-1,2-cis)-1,2-dihydroxyindolizidine—two precursors of swainsonine in the fungus pathway—in the shoots of the plant, Harris et al. proposed that the biosynthetic pathway of swainsonine in the locoweed is nearly identical to that of the fungus.[13]

Synthesis

Despite the small size of swaisonine, the synthesis of this molecule and its analogues is quite challenging due to the presence of four chiral centers. In most cases, synthesis implies the use of sugars, chiral aminoacids as starting compounds, or chiral catalysts to induce chirality.The swainsonine synthesis was systemazed by three common precursors: 8-oxy-hexahydroindolizines, N-protected-3-oxy-2-substituted-piperidines and 2-substituted-pyrrolidine-3,4-protected-diols.[14]

Livestock losses

Because chronic intoxication with swainsonine causes a variety of neurological disorders in livestock,[15] these plant species are known collectively as locoweeds. Other effects of intoxication include reduced appetite and consequent reduced growth in young animals and loss of weight in adults, and cessation of reproduction (loss of libido, loss of fertility, and abortion).[16]

Potential uses

Swainsonine has a potential for treating cancers such as glioma[17] and gastric carcinoma.[18] However, a phase II clinical trial of GD0039 (a hydrochloride salt of swainsonine) in 17 patients with renal carcinoma was discouraging.[19] Swainsonine's activity against tumors is attributed to its stimulation of macrophages.[20]

Swainsonine also has potential uses as an adjuvant for anti-cancer drugs and other therapies in use. In mice, swainsonine reduces the toxicity of doxorubicin, suggesting that swainsonine might enable use of higher doses of doxorubicin.[21] [22] Swainsonine may promote restoration of bone marrow damaged by some types of cancer treatments.[23] [24]

Molecular mechanism

The inhibitory effect of swainsonine on Golgi Mannosidase II (GMII) was proposed to be due to its ability to bind in the GMII binding pocket in a similar fashion as the natural GMII substrate in its transition state.[25] Later, it was shown that the binding pattern of the swainsonine molecule resembles that of the Michaelis complex of mannose and only the protonated, charge positive swainsonine molecule binds similarly to the substrate in its transition state.[26] The actual state in which swainsonine binds in the mannosidase remains undetermined and is most likely dependent on the pH at which the enzyme operates.[26]

See also

Notes and References

  1. Web site: NCATS Inxight: Drugs. drugs.ncats.io. en. 2020-01-22.
  2. Stegelmeier BL, Molyneux RJ, Elbein AD, James LF . The lesions of locoweed (Astragalus mollissimus), swainsonine, and castanospermine in rats. Veterinary Pathology. 32. 3. 289–98. May 1995. 7604496. 10.1177/030098589503200311. 45016726. free.
  3. Dorling PR, Huxtable CR, Colegate SM . Inhibition of lysosomal alpha-mannosidase by swainsonine, an indolizidine alkaloid isolated from Swainsona canescens . . 191 . 2 . 649–51 . November 1980 . 6786280 . 1162258 . 10.1042/bj1910649 .
  4. Zhang, L., Wu, R., Mur, L.A., Guo, C., Zhao, X., Meng, H., Yan, D., Zhang, X., Guan, H., Han, G. and Guo, B., 2023. Assembly of high‐quality genomes of the locoweed Oxytropis ochrocephala and its endophyte Alternaria oxytropis provides new evidence for their symbiotic relationship and swainsonine biosynthesis. Molecular Ecology Resources, 23(1), pp.253-272.
  5. Lu. Hao. Quan. Haiyun. Ren. Zhenhui. Wang. Shuai. Xue. Ruixu. Zhao. Baoyu. The Genome of Undifilum oxytropis Provides Insights into Swainsonine Biosynthesis and Locoism. Scientific Reports. 6. 1. 2016. 30760. 2045-2322. 10.1038/srep30760. 27477109. 4967851. 2016NatSR...630760L. free.
  6. Sim . Kim Lan . Perry . David . Swainsonine production by Metarhizium anisopliae determined by means of an enzymatic assay . Mycological Research . 1 September 1995 . 99 . 9 . 1078–1082 . 10.1016/S0953-7562(09)80776-4 .
  7. Cook D, Gardner DR, Grum D, Pfister JA, Ralphs MH, Welch KD, Green BT . Swainsonine and endophyte relationships in Astragalus mollissimus and Astragalus lentiginosus . . 59 . 4 . 1281–7 . February 2011 . 21214242 . 10.1021/jf103551t .
  8. 27436221 . 10.1021/acs.jafc.6b02390 . 64 . 31 . Analysis of Swainsonine and Swainsonine N-Oxide as Trimethylsilyl Derivatives by Liquid Chromatography-Mass Spectrometry and Their Relative Occurrence in Plants Toxic to Livestock . 2016 . J Agric Food Chem . 6156–62 . Gardner . DR . Cook . D.
  9. Cook D, Beaulieu WT, Mott IW, Riet-Correa F, Gardner DR, Grum D, Pfister JA, Clay K, Marcolongo-Pereira C . Production of the alkaloid swainsonine by a fungal endosymbiont of the Ascomycete order Chaetothyriales in the host Ipomoea carnea . . 61 . 16 . 3797–803 . April 2013 . 23547913 . 10.1021/jf4008423 .
  10. Barbosa. Rossemberg C.. Riet-Correa. Franklin. Lima. Everton F.. Medeiros. Rosane M.T.. Guedes. Karla M.R.. Gardner. Dale R.. Molyneux. Russell J.. Melo. Lúcio E.H. de. Experimental swainsonine poisoning in goats ingesting Ipomoea sericophylla and Ipomoea riedelii (Convolvulaceae). Pesquisa Veterinária Brasileira. 27. 10. 2007. 409–414. 0100-736X. 10.1590/S0100-736X2007001000004. free.
  11. Mendonça. Fábio S.. Silva Filho. Givaldo B.. Chaves. Hisadora A.S.. Aires. Lorena D.A.. Braga. Thaiza C.. Gardner. Dale R.. Cook. Daniel. Buril. Maria T.. Detection of swainsonine and calystegines in Convolvulaceae species from the semiarid region of Pernambuco. Pesquisa Veterinária Brasileira. 38. 11. 2018. 2044–2051. 1678-5150. 10.1590/1678-5150-pvb-5945. free.
  12. Mendonça FS, Albuquerque RF, Evêncio-Neto J, Freitas SH, Dória RG, Boabaid FM, Driemeier D, Gardner DR, Riet-Correa F, Colodel EM . Alpha-mannosidosis in goats caused by the swainsonine-containing plant Ipomoea verbascoidea . . 24 . 1 . 90–5 . January 2012 . 22362938 . 10.1177/1040638711425948 . free .
  13. Harris. Constance M.. Bruce C. Campbell . Russell J. Molyneux . Thomas M. Harris . Biosynthesis of swainsonine in the diablo locoweed (Astragalus oxyphyrus). Tetrahedron Letters. 1988. 29. 38. 4815–4818. 10.1016/S0040-4039(00)80616-4.
  14. Drogalin . Artem . 2022-07-21 . Advances in the Chemistry of (−)-D-Swainsonine . ChemistrySelect . en . 7 . 27 . 10.1002/slct.202201905 . 250930070 . 2365-6549.
  15. News: THE DARLING PEA. . . 14 May 1897 . 16 May 2014 . 5 . National Library of Australia.
  16. Panter KE, James LF, Stegelmeier BL, Ralphs MH, Pfister JA . Locoweeds: effects on reproduction in livestock. Journal of Natural Toxins. 8. 1. 53–62. February 1999. 10091128.
  17. Sun JY, Yang H, Miao S, Li JP, Wang SW, Zhu MZ, Xie YH, Wang JB, Liu Z, Yang Q . Suppressive effects of swainsonine on C6 glioma cell in vitro and in vivo. Phytomedicine. 16. 11. 1070–4. May 2009. 19427771. 10.1016/j.phymed.2009.02.012.
  18. Sun JY, Zhu MZ, Wang SW, Miao S, Xie YH, Wang JB . Inhibition of the growth of human gastric carcinoma in vivo and in vitro by swainsonine. Phytomedicine. 14. 5. 353–9. May 2007. 17097281. 10.1016/j.phymed.2006.08.003.
  19. Shaheen PE, Stadler W, Elson P, Knox J, Winquist E, Bukowski RM . Phase II study of the efficacy and safety of oral GD0039 in patients with locally advanced or metastatic renal cell carcinoma. Investigational New Drugs. 23. 6. 577–81. December 2005. 16034517. 10.1007/s10637-005-0793-z. 33471927.
  20. Das PC, Roberts JD, White SL, Olden K . Activation of resident tissue-specific macrophages by swainsonine. Oncology Research. 7. 9. 425–33. 1995. 8835286.
  21. Oredipe OA, Furbert-Harris PM, Laniyan I, Green WR, Griffin WM, Sridhar R . Mice primed with swainsonine are protected against doxorubicin-induced lethality. Cellular and Molecular Biology (Noisy-le-Grand, France). 49. 7. 1089–99. November 2003. 14682391.
  22. Oredipe OA, Furbert-Harris PM, Laniyan I, Green WR, Griffin WM, Sridhar R . Coadministration of swainsonine and doxorubicin attenuates doxorubicin-induced lethality in mice. Cellular and Molecular Biology (Noisy-le-Grand, France). 49. 7. 1037–48. November 2003. 14682385.
  23. Oredipe OA, Furbert-Harris PM, Laniyan I, Griffin WM, Sridhar R . Limits of stimulation of proliferation and differentiation of bone marrow cells of mice treated with swainsonine. International Immunopharmacology. 3. 10–11. 1537–47. October 2003. 12946451. 10.1016/S1567-5769(03)00186-3.
  24. Klein JL, Roberts JD, George MD, Kurtzberg J, Breton P, Chermann JC, Olden K . Swainsonine protects both murine and human haematopoietic systems from chemotherapeutic toxicity. British Journal of Cancer. 80. 1–2. 87–95. April 1999. 10389983. 10.1038/sj.bjc.6690326. 2363022.
  25. Petersen . Luis . Ardèvol . Albert . Rovira . Carme . Reilly . Peter J. . Molecular Mechanism of the Glycosylation Step Catalyzed by Golgi α-Mannosidase II: A QM/MM Metadynamics Investigation . Journal of the American Chemical Society . 23 June 2010 . 132 . 24 . 8291–8300 . 10.1021/ja909249u . 20504027 .
  26. Sladek . V. . Kóňa . J. . Tokiwa . H. . In silico analysis of interaction pattern switching in ligand⋯receptor binding in Golgi α-mannosidase II induced by the protonated states of inhibitors . Physical Chemistry Chemical Physics . 2017 . 19 . 19 . 12527–12537 . 10.1039/c7cp01200d . 28470253 . 2017PCCP...1912527S .

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