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Swainsonine
Swainsonine
Swainsonine
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Swainsonine
Names
Preferred IUPAC name
(1S,2R,8R,8aR)-Octahydroindolizine-1,2,8-triol
Other names
Tridolgosir
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.123.531 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C8H15NO3/c10-5-2-1-3-9-4-6(11)8(12)7(5)9/h5-8,10-12H,1-4H2/t5-,6-,7-,8-/m1/s1 checkY
    Key: FXUAIOOAOAVCGD-WCTZXXKLSA-N checkY
  • InChI=1/C8H15NO3/c10-5-2-1-3-9-4-6(11)8(12)7(5)9/h5-8,10-12H,1-4H2/t5-,6-,7-,8-/m1/s1
    Key: FXUAIOOAOAVCGD-WCTZXXKLBP
  • InChI=1S/C8H15NO3/c10-5-2-1-3-9-4-6(11)8(12)7(5)9/h5-8,10-12H,1-4H2/t5-,6-,7-,8-/m1/s1
    Key: FXUAIOOAOAVCGD-WCTZXXKLSA-N
  • C1C[C@H]([C@@H]2[C@@H]([C@@H](CN2C1)O)O)O
Properties
C8H15NO3
Molar mass 173.2
Melting point 143 to 144 °C (289 to 291 °F; 416 to 417 K)
10 mg/1 mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

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

[edit]

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.[citation needed]

The pharmacological properties of this product have not been fully investigated.[citation needed]

Sources

[edit]

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][3]
Convolvulaceae Jacquemontia corymbulosa, Ipomoea verbascoidea, I. subincana, I. megapotamica, I. rosea, I. carnea, I. sericophylla, I. riedelii[9][10][11][12]
Swainsonine biosynthesis scheme

Biosynthesis

[edit]

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

[edit]

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]

Swainsonine synthesis from common precursors[14]

Livestock losses

[edit]

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

[edit]

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

[edit]

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

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Swainsonine

View on Grokipedia
from Grokipedia
Swainsonine (C₈H₁₅NO₃) is a naturally occurring indolizidine that functions as a potent and reversible inhibitor of α-mannosidases, enzymes involved in processing, particularly in the and Golgi apparatus. First isolated in from the Australian plant Swainsona canescens, it is produced by certain plants in the , , and families, as well as by endophytic fungi such as Rhizoctonia leguminicola. As the primary toxin in s like Astragalus and Oxytropis species, swainsonine causes locoism in grazing animals, leading to symptoms including intention tremors, , reproductive dysfunction, and potentially death through disruption of lysosomal function and metabolism. The alkaloid's polyhydroxylated structure enables it to mimic mannose-containing oligosaccharides, thereby binding to and inhibiting α-mannosidase I and II, which alters N-linked and induces the formation of hybrid-type oligosaccharides. This mechanism not only underlies its toxicity but also contributes to its immunomodulatory effects, such as activation of natural killer cells and enhancement of activity, as observed in preclinical studies. In pharmacological research, swainsonine has demonstrated antineoplastic potential by inhibiting tumor , , and , while potentiating the effects of chemotherapeutic agents through pathways involving stress, induction, and modulation. It also exhibits chemoprotective and hemorestorative properties, protecting cells from cytotoxic damage in murine models, which has prompted investigations into its use as an adjunct in cancer . However, its therapeutic application remains limited due to potential adverse effects, including exacerbation of certain cancers in specific models and challenges in synthesis and delivery. Biosynthetic pathways for swainsonine have been elucidated in fungi, involving hybrid nonribosomal peptide-polyketide clusters, offering prospects for biotechnological production.

Chemical Properties

Molecular Structure

Swainsonine is classified as an indolizidine alkaloid, characterized by a bicyclic [4.3.0] ring system formed by the fusion of a five-membered ring and a six-membered ring, with the atom serving as one of the bridgehead atoms (standard numbering places the fusion at positions 4a and 8a, with N adjacent in the piperidine ring). This core structure, known as octahydroindolizine, provides the foundational scaffold for its biological interactions. The molecule is polyhydroxylated, featuring three hydroxyl groups at the C-1, C-2, and C-8 positions, resulting in the molecular formula C₈H₁₅NO₃. Its systematic name is (1S,2R,8R,8aR)-octahydroindolizine-1,2,8-triol, reflecting the specific absolute . These hydroxyl substituents are arranged in a configuration that mimics certain moieties, contributing to its function as a glycosidase inhibitor. Swainsonine contains four chiral centers at C-1, C-2, C-8, and the C-8a, with the (1S,2R,8R,8aR) configuration essential for its potent and selective binding to target ; alterations in this , as seen in synthetic analogs, significantly reduce inhibitory efficacy. Compared to the related indolizidine castanospermine, which bears four hydroxyl groups at C-1, C-6, C-7, and C-8 with the (1S,6S,7R,8R,8aR) configuration and formula C₈H₁₅NO₄, swainsonine features a hydroxyl at C-2 instead of at C-6 and C-7, resulting in a rather than tetrol structure that influences their distinct substrate mimicry and enzyme specificity.

Physical and Chemical Characteristics

Swainsonine has the molecular formula C₈H₁₅NO₃ and a molecular weight of 173.21 g/mol. It appears as a white crystalline solid. The compound melts at 143–144 °C. Swainsonine exhibits high in , approximately 10 mg/mL, and is also soluble in solvents such as , , DMSO, and DMF at similar concentrations, though less so in PBS (pH 7.2) at 0.25 mg/mL. It is stable under neutral pH conditions but shows degradation in strong acidic or basic environments, as demonstrated in stability studies across pH ranges from 2 to 12. In biological fluids, swainsonine maintains stability as a small, polar , resisting owing to its rigid indolizidine ring structure. The natural enantiomer, (-)-swainsonine, displays a specific optical rotation of [α]_D^{25} = -85.1° (c 0.6, MeOH). Spectroscopic characterization includes ^1H NMR data in D_2O showing key proton shifts, such as δ 3.85 (dd, H-2), δ 3.72 (t, H-1), and δ 3.45 (dd, H-8), confirming the polyhydroxylated indolizidine framework. In the IR spectrum, characteristic absorptions for hydroxyl groups appear around 3400 cm^{-1}, indicative of O-H stretching.

Natural Occurrence

Plant Sources

Swainsonine is primarily accumulated in several genera of plants, including Astragalus (commonly known as locoweeds), Oxytropis, Swainsona, Ipomoea, and Sida. These plants host endophytic fungi that produce the alkaloid, leading to its accumulation in plant tissues. Over 50 species of Astragalus have been identified as containing swainsonine, particularly in North and South America. Similarly, multiple Oxytropis species accumulate the compound, while Swainsona species are notable producers in Australia. In the genus Ipomoea, particularly I. carnea, swainsonine occurs in a phylogenetically distinct clade spanning multiple continents. In the Malvaceae family, swainsonine is present in species of the genus Sida, such as S. carpinifolia, a shrub native to South America (e.g., Brazil and Argentina), where it causes toxicity in grazing animals due to endophyte-mediated production of the alkaloid. Geographically, swainsonine-accumulating Astragalus species, such as A. lentiginosus, are prevalent in the , where they contribute to widespread distributions in arid and semi-arid regions. Oxytropis species are primarily found in , often overlapping with Astragalus habitats in rangelands. Swainsona species, including S. canescens, are endemic to , thriving in temperate and arid zones. For , the compound is common in tropical and subtropical areas, including (e.g., ), (e.g., ), (e.g., ), and parts of , where the plant invades wetlands and riverbanks. Sida carpinifolia is widespread in rangelands and disturbed areas. Concentrations of swainsonine in these plants vary by , tissue, growth stage, and environmental factors, typically ranging from 0.001% to 0.23% dry weight in (Astragalus and Oxytropis) seeds and foliage, with higher levels often in reproductive stages. In Ipomoea carnea leaves, mean concentrations average around 0.06% dry weight, fluctuating seasonally with higher amounts during or after rainy periods in regions like northern and northeastern . In Sida carpinifolia, concentrations have been reported up to 0.006% dry weight. These levels are sufficient to impact herbivores but can differ significantly across populations. As a , swainsonine serves an ecological role in plant defense by deterring herbivory, acting as an against generalist insects such as Spodoptera littoralis and contributing to protection against larger grazers in natural settings. This defensive function is enhanced by the alkaloid's association with vertically transmitted endophytic fungi, which may improve host plant fitness in herbivore-rich environments. Quantification of swainsonine in plant tissues commonly employs (HPLC) coupled with ultraviolet detection or (LC-MS/MS), allowing sensitive detection down to 0.001% dry weight after extraction with cation-exchange resins. These methods enable accurate assessment of toxin levels in foliage, seeds, and other parts, supporting ecological and toxicological studies.

Fungal Sources

Swainsonine is primarily produced by several endophytic and pathogenic fungi that form symbiotic or associative relationships with host plants, particularly legumes. Key species include Undifilum oxytropis, an endophytic fungus commonly associated with locoweeds such as species of Oxytropis and Astragalus, where it resides systemically in plant tissues including roots, stems, and seeds. Another significant producer is Alternaria oxytropis, an asexual endophyte isolated from Oxytropis species like O. glabra and O. sericea, which synthesizes swainsonine as a secondary metabolite within its host. Additionally, Rhizoctonia leguminicola (recently reclassified as Slafractonia leguminicola), a phytopathogenic fungus, generates swainsonine in association with red clover (Trifolium pratense), leading to toxin accumulation in the plant material. These fungi establish symbiotic relationships by colonizing roots and seeds, often through from parent to offspring, which facilitates the transfer of swainsonine to grazing animals via contaminated . In locoweeds, U. oxytropis enhances tolerance to environmental stresses while producing the , which inadvertently causes locoism in upon ingestion. Similarly, A. oxytropis integrates into the vascular system, contributing to swainsonine levels that mirror those in endophyte-infected tissues, distinguishing them from toxin-free plants. The identification of swainsonine-producing fungal endophytes began in the 1990s, with initial isolations from locoweed species revealing the role of these microbes in toxin biosynthesis, previously attributed solely to plants. Early studies successfully cultured U. oxytropis and related fungi, confirming their ability to produce the alkaloid in vitro. In fungal cultures, swainsonine production varies by species and conditions, reaching levels up to approximately 2.5 mg/g dry mass in optimized strains of Alternaria section Undifilum and related endophytes. For instance, wild-type A. oxytropis cultures yield higher concentrations compared to genetically modified variants, with precursor supplementation further elevating output. Recent findings through 2025 have elucidated genetic clusters, notably the SWN cluster containing the multifunctional swnK gene, in Alternaria species, affirming their role as primary producers even in non-legume hosts like certain morning glories where endophytic Alternaria strains contribute to toxin presence. Phylogenetic analyses of these clusters in newly characterized species, such as A. wetherii and A. swainsonii, highlight conserved biosynthetic pathways across diverse plant-fungus symbioses.

Biosynthesis

Pathway Elucidation

The biosynthetic pathway of swainsonine initiates with the of L-lysine to by lysine decarboxylase, followed by oxidation of to 5-aminopentanal, which cyclizes spontaneously to Δ¹-piperideine; subsequent reduction and carboxylation yield pipecolic acid, the key precursor for the indolizidine . This L-lysine-derived route establishes the nitrogen-containing central to swainsonine's . Pipecolic acid then condenses with units, with the oxoindolizidine core formed through cyclization and reduction mediated by the hybrid non-ribosomal peptide synthetase/ enzyme SwnK within the biosynthetic . The core undergoes stereoselective at C-1, C-2, C-7, and C-8 positions via 2-oxoglutarate-dependent dioxygenases SwnH1 and SwnH2, yielding the characteristic polyhydroxylated indolizidine framework of swainsonine. Recent advancements in 2025 achieved reconstitution of the full pathway in , delineating a 14-step sequence requiring 10 dedicated enzymes and confirming the overall flux from L-lysine to swainsonine. Complementary assays validated critical transformations, including for imine reduction and epimerization at chiral centers to establish the correct . In Rhizoctonia leguminicola, the pathway shares initial steps with slaframine biosynthesis up to the pipecolic acid intermediate before branching, with distinct downstream enzymes directing indolizidine versus elaboration. Heterologous expression in optimized E. coli strains has enhanced production yields, reaching up to 114 mg/L through co-expression of key pathway enzymes including SwnR, which boosts overall flux without altering core chemistry.

Genetic Regulation

The swainsonine biosynthetic (BGC), designated SWN, is an orthologous genomic region conserved in swainsonine-producing fungi, including endophytic species within the genera Undifilum and . This cluster encompasses seven core genes—swnA, swnH1, swnH2, swnK, swnN, swnR, and swnT—that encode key enzymes such as an aromatic aminotransferase (swnA), dioxygenases (swnH1 and swnH2), a hybrid non-ribosomal peptide synthetase/ (swnK), reductases (swnN and swnR), and a transmembrane transporter (swnT), all essential for swainsonine biosynthesis. The presence of highly similar SWN clusters across phylogenetically distant fungal orders, including Pleosporales ( and Undifilum) and (e.g., ), indicates as a mechanism for its dissemination among . The swnR gene encodes a NADB Rossmann-fold reductase essential for late-stage reduction in the pathway. In Alternaria oxytropis, a key of locoweeds, siRNA-mediated silencing of swnR reduced its expression by up to 91.5% and significantly decreased swainsonine accumulation in fungal mycelia (P < 0.01), demonstrating its critical enzymatic role without impacting fungal growth or host plant development. Complementary gene knockout experiments via homologous recombination in the same species isolated from Oxytropis glabra further confirmed this, yielding mutants with swainsonine levels approximately 83% lower than wild-type strains after 20 days of culture, alongside downregulation of SWN pathway genes like swnK and swnN. Environmental factors modulate SWN cluster expression, with upregulation observed under nitrogen limitation in endophyte-infected locoweeds, where swainsonine concentrations inversely correlate with nitrogen availability to enhance toxin production. Symbiotic interactions further induce cluster activity; for instance, swnR-silenced A. oxytropis strains forming symbioses with O. glabra in 2025 co-culture systems significantly lowered plant swainsonine content (P < 0.0001) while maintaining normal symbiosis and host growth, highlighting swnR's enzymatic influence in planta. These 2024–2025 findings from knockout and silencing approaches underscore swnR's pivotal role in swainsonine output in symbiotic contexts.

Chemical Synthesis

Early Synthetic Routes

The first total synthesis of swainsonine was reported in 1984 by Fleet, Fellows, and Smith, starting from D-glucose through a key intermediate, methyl 3-amino-3-deoxy-α-D-mannopyranoside hydrochloride. This route featured indolizidine ring closure via reductive amination and deoxygenation steps, requiring approximately 15 steps overall and affording the target in 2.7% yield from the mannopyranoside, underscoring the synthetic hurdles in assembling the bicyclic core. Subsequent routes in the 1980s leveraged chiral amino acids for enhanced stereocontrol, such as trans-4-hydroxy-L-proline in Ikota's 1987 synthesis, which utilized aziridine openings to install the piperidine ring and achieve the (1S,2R,8R,8aR) configuration. These methods typically spanned 10-12 steps with yields around 10-20%, but demanded extensive use of protecting groups like benzyl and silyl ethers to manage the reactive hydroxyls during selective functionalizations. A parallel 1984 synthesis by Yasuda, Tsutsumi, and Takaya from D-mannose employed a multi-step sequence involving imino sugar intermediates and ring closure via nucleophilic displacement, with low overall yield. Key challenges in these early efforts centered on securing the precise stereochemistry at the four chiral centers, often resulting in epimerization risks or low diastereoselectivity without chiral auxiliaries. Semisynthetic preparations complemented total syntheses by isolating swainsonine directly from locoweed (Astragalus spp.) extracts through solvent extraction and chromatography, providing milligram quantities of purified material despite variable natural concentrations, typically >0.1% dry weight in swainsonine-positive chemotypes or <0.01% in negative ones. These pioneering routes, though inefficient, supplied authentic swainsonine for initial pharmacological evaluations, confirming its α-mannosidase inhibitory activity and spurring advancements in alkaloid synthesis.

Recent Synthetic Methods

Since 2000, synthetic approaches to swainsonine have emphasized efficiency, stereocontrol, and sustainability, building on early challenges with multi-step sequences and low yields by incorporating asymmetric catalysis and metathesis reactions. A notable example is the 2006 enantioselective total synthesis by Guo and O'Doherty, which utilized an asymmetric [2+2] cycloaddition as the key step to construct the indolizidine core from a common intermediate derived from a chiral enol ether, completing the route in 13 steps with an overall yield of 17%. This method highlighted improved stereoselectivity over prior routes, enabling access to both (-)-swainsonine and (+)-6-epicastanospermine. Recent semi-synthetic approaches have incorporated biocatalytic elements from elucidated biosynthetic pathways for selective functionalization of indolizidine precursors. Efforts toward analogs have focused on C-8 modifications to enhance specificity, such as the 2015 formal asymmetric synthesis by Ma et al., which provided access to (-)-swainsonine and its 8-epimer via a chiral pool strategy from D-mannose, involving dihydroxylation and reductive amination in 10 steps from an advanced intermediate, yielding the epimer for evaluation as a more selective mannosidase inhibitor. For scalability, routes utilizing inexpensive sugar precursors like D-ribose have enabled gram-scale production; for instance, Pearson and Powers' 2002 method scaled the synthesis of a key tricyclic indolizidinol intermediate to multigram quantities (overall 12% yield for swainsonine in 14 steps), facilitating analog studies and reducing costs through commercial sugar starting materials. These developments underscore a shift toward practical, high-yield methods suitable for research and potential therapeutic scale-up.

Biological Activity

Pharmacological Effects

Swainsonine is rapidly absorbed from the gastrointestinal tract in both monogastric and ruminant animals due to its small molecular size and stability. Following oral administration, it exhibits wide tissue distribution, with notable accumulation in the liver, where concentrations can reach up to 3,947 ng/ml in sheep after chronic exposure, and in the brain, alongside other organs such as kidney and spleen. The elimination half-life in serum is approximately 16-20 hours in sheep and cattle, supporting sustained exposure during chronic ingestion. In terms of immunomodulation, swainsonine activates immune cells including macrophages, enhancing their phagocytosis and hydrogen peroxide production, while also stimulating natural killer (NK) cell activity. These effects are linked to its influence on glycoprotein processing, potentially involving interactions with mannose receptors on macrophages. Swainsonine inhibits α-mannosidase II, leading to the accumulation of hybrid-type N-glycans in cells, which results in lysosomal storage-like symptoms characterized by cytoplasmic vacuolization across various tissues. This disruption mimics lysosomal storage disorders and contributes to broader cellular dysfunction. Dose-response studies indicate toxic doses of approximately 1 mg/kg body weight in goats, with chronic low doses (e.g., 0.1-0.8 mg/kg/day) inducing weight loss and systemic effects without immediate lethality. Recent metabolomic analyses from 2024 reveal that swainsonine exposure in rat renal tubular epithelial cells disrupts amino acid metabolism pathways, particularly the degradation of valine, leucine, and isoleucine, highlighting renal-specific metabolic alterations.

Molecular Mechanism

Swainsonine primarily targets Golgi α-mannosidase II (GMII), a key enzyme in the N-glycan processing pathway, with an IC50 of approximately 20 nM. This inhibition is competitive and occurs through transition-state , where swainsonine's indolizidine resembles the oxocarbenium ion-like intermediate formed during the of α1,3- and α1,6-linked residues. The enzyme's features a (Zn2+) that polarizes the , and swainsonine exploits this by coordinating directly with the metal center, thereby preventing substrate binding and . In the binding mode, the protonated nitrogen of swainsonine forms an electrostatic interaction with the catalytic Asp204, mimicking the positive charge of the , while its hydroxyl groups establish hydrogen bonds with Zn2+, shifting the from penta- to hexa-coordinated and stabilizing the inhibitor in the -1 subsite. Additional hydrophobic stacking with residues such as Trp95, Phe206, and Tyr727 further anchors the molecule, ensuring high-affinity binding. This precise interaction disrupts the sequential cleavage required for maturing high-mannose oligosaccharides to complex types. Swainsonine also inhibits lysosomal α-mannosidase (EC 3.2.1.24) in a reversible, active site-directed manner, though with somewhat weaker potency compared to GMII, leading to the accumulation of partially processed mannose-rich oligosaccharides in lysosomes. Downstream of GMII inhibition, the untrimmed GlcNAc-Man5GlcNAc2 intermediate persists, as subsequent enzymes like N-acetylglucosaminyltransferase II cannot act effectively, resulting in hybrid-type N-glycans rather than complex structures. A 2023 study further revealed that swainsonine reduces O-GlcNAcylation of (CTSD), impairing its maturation and lysosomal function, which in turn inhibits autophagic degradation and contributes to .

Toxicology

Effects on Livestock

Swainsonine poisoning in livestock, known as locoism, manifests primarily through neurological and reproductive impairments in grazing animals such as sheep, , and horses. Clinical symptoms include , depression, staggering gait, lack of muscular coordination, intention tremors, and , often progressing to severe and unpredictable behavior in advanced stages. Reproductive failure is a hallmark effect, encompassing , abortions, and reduced rates, while vacuolar degeneration in neurons contributes to the irreversible neurological damage characteristic of the . Chronic exposure to swainsonine, typically through prolonged ingestion of as a significant portion of the diet, leads to significant productivity losses via decreased , , and reproductive inefficiencies, imposing substantial economic burdens on ranchers. Diagnosis of swainsonine-induced locoism relies on detecting detectable serum swainsonine levels in actively exposed animals, alongside reduced α-mannosidase activity and increased mannose-rich oligosaccharides in serum. Histological examination confirms the condition through observation of vacuolar changes in the Golgi apparatus of neurons and other cells, distinguishing it from other neuropathies. These diagnostic markers are most reliable during ongoing exposure, as swainsonine's short serum of less than 24 hours limits retrospective detection. Historical outbreaks underscore the syndrome's impact, with notable locoweed epidemics in the U.S. Western states during the 1980s, including severe incidents in 1980-1981 and 1984 that caused widespread livestock losses through abortions and neurological decline. In Australia, poisoning from Swainsona species has been documented since the late 1970s, affecting cattle and horses in inland regions with sporadic but recurrent cases leading to emaciation and death. Prevention strategies have advanced with sustained-release antidote formulations, such as temperature-sensitive gels incorporating "Jifang E" (an adsorbent agent), which maintain therapeutic plasma concentrations for 3-5 days post-injection and significantly mitigate swainsonine absorption in experimental models.

Cellular and Organ Toxicity

Swainsonine induces significant histopathological changes across multiple organs, primarily through its inhibition of lysosomal α-mannosidase and Golgi mannosidase II, leading to accumulation of mannose-rich oligosaccharides and subsequent cellular vacuolation. In the brain, particularly in Purkinje cells of the cerebellum, lysosomal vacuolation is a prominent feature observed in affected goats, where electron microscopy reveals dilated lysosomes filled with storage material, contributing to neuronal dysfunction and ataxia. This vacuolar degeneration is evident in experimental models where goats were dosed with swainsonine-containing plants like Turbina cordata, resulting in diffuse vacuolation and clinical signs such as intention tremors and hypermetria. In the liver, swainsonine triggers and structural damage, with studies in mice demonstrating hepatic inflammatory responses driven by disruptions in and alterations, potentially progressing to fibrotic changes in chronic exposure scenarios. involvement manifests as proximal tubular epithelial degeneration and cytoplasmic vacuolar change, with moderate diffuse involvement and evidence of tubular regeneration in affected tissues, as seen in histopathological examinations of swainsonine-poisoned . These changes highlight swainsonine's role in inducing lysosomal storage-like at the organ level, distinct from its enzymatic effects at the molecular scale. Recent analyses of swainsonine-exposed rat renal tubular epithelial cells reveal profound disruptions in metabolic pathways, including perturbations in with elevated levels of certain , alongside downregulation of pathways linked to energy production such as those involving TCA cycle intermediates. Specifically, treatment with 0.8 mg/mL swainsonine for 12 hours identified 2,170 differential metabolites, with upregulation in -related pathways and impacts on biosynthesis, underscoring metabolic imbalance as a key contributor to renal toxicity. Swainsonine promotes cell death through induction, mediated by (ER) stress and inhibition of the pathway, as evidenced in neuronal and renal models from 2023 studies. In hippocampal neurons, swainsonine activates ER stress markers while suppressing -mediated , leading to vacuolar degeneration and apoptotic cascades. Similarly, in cells, swainsonine represses proliferation and induces by inhibiting the PI3K/AKT/ signaling axis, highlighting its role in cellular toxicity beyond lysosomal effects. The toxicity profile of swainsonine exhibits dose- and duration-dependent reversibility; acute exposure allows partial recovery of lysosomal enzyme activity and resolution of vacuolation upon cessation, as observed in models where antioxidants like ascorbic acid mitigate neuronal damage. However, chronic administration leads to irreversible neurodegeneration, with permanent loss of Purkinje neurons and in the of goats and rats, emphasizing the progressive nature of lysosomal storage accumulation. Goat and rat models have been instrumental in confirming Golgi swelling as a histopathological hallmark of swainsonine toxicity, where inhibition of Golgi mannosidase II results in organelle dilation and impaired glycoprotein processing, observable in neuronal tissues alongside lysosomal changes. Experimental dosing in rats demonstrates marked reduction in Golgi enzyme activity, correlating with swelling and contributing to the broader vacuolar pathology in brain and kidney.

Potential Applications

Anticancer Research

Swainsonine exerts its anticancer effects primarily by inhibiting Golgi α-mannosidase II, which disrupts N-linked in tumor cells, leading to altered cell surface glycoproteins that impair tumor growth, invasion, and . This inhibition sensitizes cancer cells to chemotherapeutic agents; for instance, in human cell lines, swainsonine potentiates the cytotoxic effects of by enhancing and reducing cell viability without significantly affecting normal cells. Preclinical studies have demonstrated swainsonine's ability to inhibit in gastric models, such as in nude mice bearing human SGC-7901 tumors, where it suppressed tumor growth and metastatic spread through enhanced immune responses and direct antiproliferative effects. Additionally, a 2023 study revealed that swainsonine blocks autophagic degradation in cancer cells by reducing O-GlcNAcylation of , leading to lysosomal dysfunction and , which could amplify antitumor responses. A Phase II in 2005 evaluated oral swainsonine (GD0039) in 17 patients with advanced , but it showed no objective antitumor responses, with all participants discontinuing due to disease progression or toxicity, including , , and ; no new clinical trials have been reported since 2020. To address these limitations, researchers have developed swainsonine analogs, such as C-6 fluorinated , that exhibit reduced inhibition of lysosomal α-mannosidase while maintaining potency against Golgi α-mannosidase II, potentially improving specificity and minimizing off-target toxicity in cancer therapy. Key challenges in swainsonine's clinical translation include its narrow therapeutic window, driven by dose-limiting toxicities that overlap with anticancer benefits. A 2021 study in models demonstrated between swainsonine and in a syngeneic B16F10 model, where swainsonine disrupts PD-L1 N- to enhance antibody efficacy and inhibit tumor growth; this potential was discussed in a 2024 review. As of 2025, further research has explored swainsonine in reducing PD-1 glycosylation to improve outcomes.

Other Therapeutic and Preventive Uses

Swainsonine has demonstrated immunomodulatory properties that enhance production, including interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α), which may support immune responses against viral infections. In human lymphocytes, swainsonine treatment increases mitogen-induced IL-2 production and receptor expression, promoting T-cell activation and proliferation. This effect extends to macrophages, where swainsonine boosts , generation, and overall immune cell activity. Early preclinical studies in the evaluated these properties in models of acquired immunodeficiency syndrome (AIDS), using swainsonine extracted from plants like Ipomoea carnea to assess potential benefits in countering in mice. In the context of lysosomal storage disorders, swainsonine serves primarily as an experimental tool to mimic α-mannosidosis by inhibiting lysosomal α-mannosidase, allowing researchers to study disease pathogenesis in preclinical models such as mice. While direct therapeutic application to correct glycosylation defects remains exploratory, mouse models of α-mannosidosis have been used to test enzyme replacement therapies that address the underlying enzyme deficiency exacerbated by swainsonine-like inhibition. These models highlight swainsonine's role in inducing vacuolar degeneration and storage accumulation, informing strategies for metabolic interventions. To prevent swainsonine in , known as locoism, a sustained-release injection developed in 2023 provides prolonged protection by maintaining therapeutic drug levels, significantly reducing intoxication rates compared to traditional powders or oral supplements. Swainsonine exhibits pro-inflammatory effects in certain models by modulating release and cellular responses. A 2024 study linked swainsonine to via gut microbiota disruption and increased , leading to elevated (LPS) levels and proinflammatory . A 2025 study reported that swainsonine protects human thyrocytes from Fas-induced , suggesting potential benefits in autoimmune conditions. Future directions include leveraging the biosynthetic (BGC) identified in swainsonine-producing fungi for targeted production in therapeutic contexts. The SWN cluster, conserved across species like , enables for controlled synthesis, potentially integrating with vectors to deliver swainsonine precisely to immune or inflammatory sites without toxicity risks. This approach builds on recent characterizations of BGC components, such as the nonribosomal peptide-polyketide hybrid, to refine immunomodulatory applications.

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