Modeccin

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Modeccin is a toxic lectin, a group of glycoproteins capable of binding specifically to sugar moieties. Different toxic lectins are present in seeds of different origin. Modeccin is found in the roots of the African plant Adenia digitata . These roots are often mistaken for edible roots, which has led to some cases of intoxication. Sometimes the fruit is eaten, or a root extract is drunk as a manner of suicide. [1] [2]

Contents

Structure and reactivity

Modeccin consists of two subunits that are bound by a disulfide linkage, the intact protein has a molecular weight of approximately 57-63  kDa. [3] When treated with mercaptoethanol the chains can be dissociated into two subunits, [4] subunit A with a mass of 25-28 kDa and subunit B with a mass of 31-35 kDa. [4]

The A-chain is called the effectomer and possesses ribosomal-inactivating properties. [5] The B-chain contains the carbohydrate binding site and it is termed the haptomer. While the intact toxin molecules have potent cytotoxic effects on cells, they exhibit no ribosomal inactivating activity on ribosomes in a cell-free system. By contrast, reduction of the toxin with a disulfide reducing agent creates the opposite effects. Reduced, dissociated toxin subunits inhibit ribosomal activity in cell-free systems, but they have no effect on intact cells.

The reason for these properties is due to the toxin's mode of action. Toxin molecules bind through saccharide recognition sites on the B-chain to particular β-galactosyl-containing glycoprotein or glycolipid components on the surface of cell membranes. In animals that are sensitive to these toxins these polysaccharides are present in virtually all cell types. The toxin binds to cell-surface polysaccharide receptors with a high affinity (Ka in the range of 107–108/M). When the toxin binds to the cell, the A-chain enters through either active transport or endocytosis. Once inside the cell the A-chain enters the cytoplasmic space, binds to the 60S ribosomal subunit and enzymatically inactivates it. The mechanism is catalytic because of this one toxin molecule is enough to disrupt protein synthesis and kill the target cell. [6]

Cytotoxic lectins including modeccin act in a similar manner as ricin, a well understood toxic lectin, though each one has a different saccharide binding specificity. [7]

Cytotoxic lectins include ricin, abrin, modeccin, volkensin (least toxic, 10 and 40 times less cytotoxic than ricin and modeccin respectively.) and viscumin (10 times less cytotoxic than ricin). [8]

Comparison of the parenteral lethality of ricin and related toxins in laboratory mice [8] :439

Toxin LD50 (mg/kg)Reference
Ricin 0.8-10 [9] [10] [11] [2] [12] [13]
Abrin 0.6-20 [14] [15] [16] [13] [17]
Modeccin2.0-5.3 [18] [19] [13]
Volkensin 1.7 [20] [13]
Viscumin 2.4 [16]

Hybrids

Synthetically produced toxins and genetically engineered toxin chimeras are areas of emerging interest because of their possible application as new medical modalities (e.g., IgTs) and powerful research tools, as well as their potential misuse as toxin weapons to confuse traditional medical countermeasures (Olsnes and Pihl, 1986; Millard, 2005). Hybrid molecules were prepared from the A- and B-chains of the toxic lectins ricin and modeccin by dialyzing mixtures of isolated chains to allow a disulfide bridge to be formed between them. Whereas the hybrid consisting of ricin A-chain and modeccin B-chain was non-toxic, the converse hybrid, modeccin A-chain/ricin B-chain, was even more toxic than were the parent toxins, native ricin and modeccin. [4]

Extraction

Extraction of modeccin from the roots of Adenia digitata follows the following procedure. It is firstly chopped into small pieces and then soaked in a sodium chloride solution overnight. It is then homogenised in a Waring Blender and left standing overnight. A cheesecloth is used to wring out all moisture from the mixture. The extract was left standing again overnight, and the remaining supernatant was obtained through centrifugation. The dissolved proteins were precipitated by saturation of the supernatant using ammonium sulfate. The proteins were obtained through centrifugation, redissolving in H2O and dialysis against running water for two days. Finally, the precipitate was removed via low speed centrifugation and the supernatant was freeze-dried. [3]

The extract was fractioned using a Sephadex column. The different fractions were assayed for toxicity to mice, to which the most toxic fraction was pooled and subsequently applied to a DEAE-(diethylaminoethyl)-column. The bound proteins, including modeccin, were eluted and fractionised using a gradient of sodium chloride in solution. Again, the fractions were assayed for toxicity to mice, to which the most toxic fraction was pooled and analysed by Gel Electrophoresis. To better follow the protein during further purification, labelling using 125I is done via the lactoperoxidase method. This does not affect toxicity. [3]

Further purification using affinity chromatography with immobilised glycoproteins. Affinity was increased by glycoprotein-treatment with neuraminidase, enzymes that cleave glycosidic linkages of neuraminic acids. Elution of the proteins from the column was effectuated using lactose. Dialysis of the eluted proteins removed the lactose. The different fractions were assayed for toxicity to mice. [3]

Gel electrophoresis of the fractions was carried out on a polyacrylamide gel. Samples were made containing sodium dodecyl sulphate, and in some cases small amounts of mercapto- ethanol. A molecular weight of approximately 63 kDa is found in the protein fractions, with traces of 38 kDa and 28 kDa. These trace-fractions are more apparent in mercaptoethanol treated protein fractions. This confirms that modeccin consists of two protein chains of 28 and 38 kDa respective, linked via a disulfide bond. [3]

Mechanism of action

Modeccin inhibits protein synthesis by inactivating the 60S ribosomal subunit. Evidence shows that the toxin inhibits both initiation as elongation of peptide chains. The toxin only attacks eukaryotic ribosomes, bacteria are resistant.

The B-chain

The B-chain has saccharide recognition sites for particular ß-galactosyl-containing glycopro-teins or glycolipid compounds on the cell membrane.

Modeccin B-chain enters the cytosol after a delay, [8] since most of the time it is present in intracellular vesicles. Without the Golgi complex, the B-chain cannot enter the cytosol and therefore loses its toxicity. [21] [22] It only enters the cytosol after it has reached the Golgi complex. Modeccin requires a low pH for entry into the cell. Below pH of 6.0, modeccin can't enter the cell via endocytosis. It is also known that entry to the cytosol require Ca2+-ions.

The A-chain

Research has shown that one toxin A-chain can inactivate a large number of ribosomes, this suggests that the toxin acts by catalytic mechanism. The nature of the enzymatic activity of the A-chain is still not completely clear, it is likely that the A-chain acts as hydrolytic enzyme. Possibly by removing a minor functional group like methyl or phosphate. Experimental data shows that modeccin kills cells by inactivating the 60S ribosomal subunit, [4] [21] [23] however the possibility cannot be excluded that the poison also acts on other parts of the cell.

In studies with cell free systems it was shown that only free A-chains inhibit protein synthesis, when the A-chain was bound to the B-chain the toxin was not active. [5] The toxin acts on the ribosomes at, or close to the binding site of Elongation Factor 2 (EF2) and effectuates a modification at this site resulting in lower affinity of EF2 on that site. The ribosomes are sensitized to modeccin if EF2 is unbound to GTP. [23] A conformational change to the 60S ribosomal subunit is induced by EF2, which is favourable for the action of modeccin B-chain. [23]

Effects on animals

Modeccin facilitates destruction of dopaminergic neurons in the ipsilateral substantia nigra and intralaminar thalamus in mice central nervous system (CNS). Modeccin is therefore a more potent suicide transport agent than ricin, as ricin is unable to bind to plasma membranes of CNS axon terminals. Direct injection of modeccin into the CNS effectuated local necrosis. [7]

Modeccin exhibits the same toxicity to hepatocytes (liver cells) in vivo as in vitro. It penetrates the hepatocytes and damages the 60s ribosomal subunits. Vesiculation and degranulation of the rough endoplasmatic reticulum after 6 hours of poisoning, total fragmentation after 24 hours of poisoning. Not only the ribosomes are affected, also mitochondria showed damage after modeccin poisoning.

Metabolism

The mechanism of metabolism of modeccin has not been investigated but presumably consists of proteolysis. Free toxin is removed by primarily the liver and kidneys or may be degraded through cellular internalization via lysosomes. The lysosomes carry digestive enzymes, including several proteases that can degrade the modeccin. [24]

Counteracting toxicity

Saccharide binding competition

Mono- and disaccharides, specifically galactose and lactose are potent binding inhibitors of modeccin. This is related to the necessity of terminal galactose residues in modeccin binding sites on cell-membranes.

Brefeldin A

Treatment with Brefeldin A (BFA) inhibits the cytotoxicity of modeccin, [25] by disrupting the Golgi apparatus. Brefeldin A blocks transport from the Endoplasmatic Reticulum and inhibits vesicle formation in the Golgi apparatus. Nucleotide exchange into ADP-ribosylation factor (ARF) is inhibited by BFA, thus preventing assembly of cytosolic coat proteins on target membranes. Without vesicle formation that transport modeccin from the Golgi apparatus into the cytosol, modeccin can't enter the cytosol. [22]

Degree of acidity

Intravesicular elevation of pH, facilitated by treatment with NH3Cl, inhibits cytotoxicity of modeccin. [4] [26] Also, incorporation of ionophores like Monensin in the cells facilitates elevation of pH. [4] This is because of their capability of reversible ion-binding and their lipophilic nature.

Ceramide analogs

The protective effect of ceramide analogs and related sphingolipids, shown in figure 5, is observed in cytotoxin activity of modeccin. They do not affect the binding and internalization of modeccin but do affect the intracellular protein transport through the Golgi complex. C2-cer, C6-cer and C8-cer protect against modeccin toxicity, but the former and the latter less effective than C6-cer. The naturally occurring C18-cer has no effect on modeccin toxicity, as well as sphingosine and sphingomyelin. [25]

Related Research Articles

Ribosome Intracellular organelle consisting of RNA and protein functioning to synthesize proteins

Ribosomes are macromolecular machines, found within all living cells, that perform biological protein synthesis. Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to form polypeptide chains. Ribosomes consist of two major components: the small and large ribosomal subunits. Each subunit consists of one or more ribosomal RNA (rRNA) molecules and many ribosomal proteins. The ribosomes and associated molecules are also known as the translational apparatus.

Ricin Type of toxic lectin

Ricin ( RY-sin) is a lectin (a carbohydrate-binding protein) and a highly potent toxin produced in the seeds of the castor oil plant, Ricinus communis. The median lethal dose (LD50) of ricin for mice is around 22 micrograms per kilogram of body weight via intraperitoneal injection. Oral exposure to ricin is far less toxic. An estimated lethal oral dose in humans is approximately 1 milligram per kilogram of body weight.

Shiga toxin Family of related toxins

Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, expressed by genes considered to be part of the genome of lambdoid prophages. The toxins are named after Kiyoshi Shiga, who first described the bacterial origin of dysentery caused by Shigella dysenteriae. Shiga-like toxin (SLT) is a historical term for similar or identical toxins produced by Escherichia coli. The most common sources for Shiga toxin are the bacteria S. dysenteriae and some serotypes of Escherichia coli (STEC), which includes serotypes O157:H7, and O104:H4.

Lectin Carbohydrate-binding protein

Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in recognition at the cellular and molecular level and play numerous roles in biological recognition phenomena involving cells, carbohydrates, and proteins. Lectins also mediate attachment and binding of bacteria, viruses, and fungi to their intended targets.

<i>Adenia</i> Genus of plants

Adenia is a genus of flowering plants in the passionflower family, Passifloraceae. It is distributed in the Old World tropics and subtropics. The centers of diversity are in Madagascar, eastern and western tropical Africa, and Southeast Asia. The genus name Adenia comes from "aden", reported as the Arabic name for the plant by Peter Forsskål, the author of the genus.

Abrin Chemical compound

Abrin is an extremely toxic toxalbumin found in the seeds of the rosary pea, Abrus precatorius. It has a median toxic dose of 0.7 micrograms per kilogram of body mass when given to mice intravenously. The median toxic dose for humans ranges from 10 to 1000 micrograms per kilogram when ingested and is 3.3 micrograms per kilogram when inhaled.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recycling.


Gelonin is known as the "ribosome-inactivating protein" and is currently on the radar of a lot of researchers, as a potential treatment for cancer. Gelonin is a protein toxin of approximately 30 kDa found in the seeds of the Himalayan plant Gelonium multiflorum. In cell-free systems gelonin exerts powerful N-glycosidase activity on the 28S rRNA unit of eukaryotic ribosomes by cleaving out adenine at the 4324 site. Gelonin lacks carbohydrate-binding domain, which are comprised as Beta-chains, so it is unable to cross the plasma membrane, making it highly effective in cell free systems.

The AB5 toxins are six-component protein complexes secreted by certain pathogenic bacteria known to cause human diseases such as cholera, dysentery, and hemolytic–uremic syndrome. One component is known as the A subunit, and the remaining five components are B subunits. All of these toxins share a similar structure and mechanism for entering targeted host cells. The B subunit is responsible for binding to receptors to open up a pathway for the A subunit to enter the cell. The A subunit is then able to use its catalytic machinery to take over the host cell's regular functions.

Pancreatic ribonuclease

Pancreatic ribonucleases are pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles.

Prokaryotic small ribosomal subunit Smaller subunit of the 70S ribosome found in prokaryote cells

The prokaryotic small ribosomal subunit, or 30S subunit, is the smaller subunit of the 70S ribosome found in prokaryotes. It is a complex of the 16S ribosomal RNA (rRNA) and 19 proteins. This complex is implicated in the binding of transfer RNA to messenger RNA (mRNA). The small subunit is responsible for the binding and the reading of the mRNA during translation. The small subunit, both the rRNA and its proteins, complexes with the large 50S subunit to form the 70S prokaryotic ribosome in prokaryotic cells. This 70S ribosome is then used to translate mRNA into proteins.

Saporin is a protein that is useful in biological research applications, especially studies of behavior. Saporin is a so-called ribosome inactivating protein (RIP), due to its N-glycosidase activity, from the seeds of Saponaria officinalis. It was first described by Fiorenzo Stirpe and his colleagues in 1983 in an article that illustrated the unusual stability of the protein.

EF-G

EF-G is a prokaryotic elongation factor involved in protein translation. As a GTPase, EF-G catalyzes the movement (translocation) of transfer RNA (tRNA) and messenger RNA (mRNA) through the ribosome.

Protein synthesis inhibitor

A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.

Ribosome-inactivating protein

A ribosome-inactivating protein (RIP) is a protein synthesis inhibitor that acts at the eukaryotic ribosome. This protein family describes a large family of such proteins that work by acting as rRNA N-glycosylase. They inactivate 60S ribosomal subunits by an N-glycosidic cleavage, which releases a specific adenine base from the sugar-phosphate backbone of 28S rRNA. RIPs exist in bacteria and plants.

Toxalbumin

Toxalbumins are toxic plant proteins that disable ribosomes and thereby inhibit protein synthesis, producing severe cytotoxic effects in multiple organ systems. They are dimers held together by a disulfide bond and comprise a lectin part which binds to the cell membrane and enables the toxin part to gain access to the cell contents. Toxalbumins are similar in structure to the toxins found in cholera, tetanus, diphtheria and botulinum; and their physiological and toxic properties are similar to those of viperine snake venom.

rRNA endonuclease is an enzyme that catalyses the hydrolysis of the phosphodiester linkage between guanosine and adenosine residues at one specific position in the 28S rRNA of rat ribosomes. This enzyme also acts on bacterial rRNA.

Volkensin is a eukaryotic ribosome-inactivating protein found in the Adenia volkensii plant. It is a glycoprotein with two subunits A and B. A subunit is linked to B subunit with disulfide bridges and non-covalent bonds. B subunit is responsible for binding to the galactosyl-terminated receptors on the cell membrane that allows the entry the A subunit of the toxin into the cell, which performs the inhibitory function. Volkensin is a galactose specific lectin that can inhibit protein synthesis in whole cells and in cell-free lysates. This protein can be included into the category of risin like toxins and it resembles modeccin, the toxin of Adenia digitata. Although very similar in composition, volkensin contains more cysteine residues and more than twice as much sugar than modeccin, due to high content of galactose and mannose. In addition, volkensin is able to inhibit protein synthesis at concentrations 10 times lower than required for modeccin. From gene sequencing analysis, volkensin was found to be coded by 1569-bp ORF, that is 523 amino acid residues without introns. The internal linker sequence is 45 bp. The active site of the A subunit contains Ser203, a novel residue that is conserved in all ribosome inactivating proteins.

Fungal ribotoxin Group of extracellular ribonucleases secreted by fungi

Fungal ribotoxins are a group of extracellular ribonucleases (RNases) secreted by fungi. Their most notable characteristic is their extraordinary specificity. They inactivate ribosomes by cutting a single phosphodiester bond of the rRNA that is found in a universally conserved sequence. This cleavage leads to cell death by apoptosis. However, since they are extracellular proteins, they must first enter the cells that constitute their target to exert their cytotoxic action. This entry constitutes the rate-determining step of their action.

Perivitellin-2 (PV2) is the second most abundant perivitellin found in the perivitelline fluid from Pomacea maculata (PmPV2) and Pomacea canaliculata (PcPV2) snail eggs. These ~172-kDa proteins are dimers of AB toxins, each composed of a carbohydrate-binding protein of the tachylectin family disulfide-linked to a pore-forming protein of the Membrane Attack Complex and Perforin (MACPF) family.

References

  1. ↑ de Ruijter A. "Adenia digitata (Harv.) Engl". PROTA4U. Plant Resources of Tropical Africa.
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  6. ↑ Hermanson GT (2013). "Antibody Modification and Conjugation". Bioconjugate Techniques. pp. 867–920. doi:10.1016/B978-0-12-382239-0.00020-0. ISBN   9780123822390.
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  10. ↑ Fodstad O, Olsnes S, Pihl A (October 1976). "Toxicity, distribution and elimination of the cancerostatic lectins abrin and ricin after parenteral injection into mice". British Journal of Cancer. 34 (4): 418–25. doi:10.1038/bjc.1976.187. PMC   2025264 . PMID   974006.
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  14. ↑ Lin JY, Chen CC, Lin LT, Tung TC (June 1969). "Studies on the toxic action of abrin". Taiwan Yi Xue Hui Za Zhi. Journal of the Formosan Medical Association. 68 (6): 322–4. PMID   5257365.
  15. ↑ Olsnes S, Pihl A (May 1973). "Isolation and properties of abrin: a toxic protein inhibiting protein synthesis. Evidence for different biological functions of its two constituent-peptide chains". European Journal of Biochemistry. 35 (1): 179–85. doi: 10.1111/j.1432-1033.1973.tb02823.x . PMID   4123356.
  16. 1 2 Olsnes S, Stirpe F, Sandvig K, Pihl A (November 1982). "Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe)". The Journal of Biological Chemistry. 257 (22): 13263–70. doi: 10.1016/S0021-9258(18)33440-9 . PMID   7142144.
  17. ↑ Dickers KJ, Bradberry SM, Rice P, Griffiths GD, Vale JA (2003). "Abrin poisoning". Toxicological Reviews. 22 (3): 137–42. doi:10.2165/00139709-200322030-00002. PMID   15181663. S2CID   20411255.
  18. ↑ Gasperi-Campani A, Barbieri L, Lorenzoni E, Montanaro L, Sperti S, Bonetti E, Stirpe F (August 1978). "Modeccin, the toxin of Adenia digitata. Purification, toxicity and inhibition of protein synthesis in vitro". The Biochemical Journal. 174 (2): 491–6. doi:10.1042/bj1740491. PMC   1185939 . PMID   708401.
  19. ↑ Stirpe F, Gasperi-Campani A, Barbieri L, Lorenzoni E, Montanaro L, Sperti S, Bonetti E (December 1977). "Inhibition of protein synthesis by modeccin, the toxin of Modecca digitata". FEBS Letters. 85 (1): 65–7. doi: 10.1016/0014-5793(78)81249-6 . PMID   598521.
  20. ↑ Stirpe F, Barbieri L, Abbondanza A, Falasca AI, Brown AN, Sandvig K, Olsnes S, Pihl A (November 1985). "Properties of volkensin, a toxic lectin from Adenia volkensii". The Journal of Biological Chemistry. 260 (27): 14589–95. doi: 10.1016/S0021-9258(17)38608-8 . PMID   3932357.
  21. 1 2 Bolognesi A, Bortolotti M, Maiello S, Battelli MG, Polito L (November 2016). "Ribosome-Inactivating Proteins from Plants: A Historical Overview". Molecules. 21 (12): 1627. doi: 10.3390/molecules21121627 . PMC   6273060 . PMID   27898041.
  22. 1 2 Sciaky N, Presley J, Smith C, Zaal KJ, Cole N, Moreira JE, Terasaki M, Siggia E, Lippincott-Schwartz J (December 1997). "Golgi tubule traffic and the effects of brefeldin A visualized in living cells". The Journal of Cell Biology. 139 (5): 1137–55. doi:10.1083/jcb.139.5.1137. PMC   2140213 . PMID   9382862.
  23. 1 2 3 Olsnes S, Abraham AK (February 1979). "Elongation-factor-2-induced sensitization of ribosomes to modeccin. Evidence for specific binding of elongation factor 2 to ribosomes in the absence of nucleotides". European Journal of Biochemistry. 93 (3): 447–52. doi: 10.1111/j.1432-1033.1979.tb12842.x . PMID   421687.
  24. ↑ "Ricin (T3D2481)". CanMedCon.
  25. 1 2 Oda T, Wu HC (November 1995). "Protective effect of cell-permeable ceramide analogs against modeccin, ricin, Pseudomonas toxin, and diphtheria toxin". Experimental Cell Research. 221 (1): 1–10. doi:10.1006/excr.1995.1346. PMID   7589233.
  26. ↑ Ghosh PC, Wu HC (February 1988). "Enhancement of cytotoxicity of modeccin by nigericin in modeccin-resistant mutant cell lines". Experimental Cell Research. 174 (2): 397–410. doi:10.1016/0014-4827(88)90310-2. PMID   3338496.
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