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Shiga toxins (Stx) are a group of type 2 ribosome-inactivating proteins (RIPs) found in Shigella dysenteriae 1 and in some serogroups of Escherichia coli. They are named after Kiyoshi Shiga, the scientist who first discovered it in 1898. These toxins have attracted significant attention due to their unique structure, diverse mechanisms of action, and potential applications in various fields.
Stx-phages exhibit significant heterogeneity and can infect various E. coli strains, leading to the production of different variants of Stx. Two major types of Stx produced from Stx-producing E. coli (STEC) were identified and named Stx-1 and Stx-2. Stx-1 shares a high degree of similarity with the Stx found in S. dysenteriae, differing in only one amino acid residue. Antibodies raised against Stx can effectively neutralize Stx-1. However, Stx-2 has limited similarity with Stx, and antibodies targeting Stx are ineffective against Stx-2.
The structure of Shiga toxin is composed of an A subunit and B subunits. The A subunit is responsible for the toxin's enzymatic activity, while the B subunits facilitate binding to specific receptors on the surface of target cells. The A subunit consists of two enzymatic domains, A1 and A2, connected by a disulfide bond. The A1 domain possesses N-glycosidase activity, which cleaves a specific adenine residue from the 28S rRNA of the eukaryotic ribosome, leading to inhibition of protein synthesis. The A2 domain plays a role in translocating the A1 domain into the cytoplasm of the target cell. The B subunits, usually organized as pentamers, are responsible for recognizing and binding to specific glycolipid receptors on the cell surface. The binding of B subunits to the receptor triggers endocytosis and internalization of the toxin into the target cell.
Figure 1 Ribbon diagram of the Stx1 crystal structure.
(Source: Melton-Celsa, A. R. et al., 2014)
The first step in the mechanism of action of Stx is the binding and internalization process. The B chains of the toxins recognize and bind to specific receptors, with the Gb3 receptor being the primary target in humans. Gb3 receptors are predominantly expressed on the surface of endothelial cells in the intestine, kidney, and brain. Once bound, the toxins are internalized by the target cells through receptor-mediated endocytosis.
After internalization, Stx requires a series of intracellular transport steps to reach their site of action. The toxins are trafficked to the endoplasmic reticulum (ER), where they undergo retrotranslocation, a process by which the A chain is transported from the ER lumen into the cytosol. This translocation step is a crucial determinant of the toxins' toxicity, as it allows the A chain to interact with its ribosomal target.
Once in the cytosol, the catalytic A chain of Stx exerts its ribosome-inactivating activity. The A chain specifically cleaves a conserved adenine residue in the α-sarcin/ricin loop (SRL) of 28S ribosomal RNA, leading to the inactivation of ribosomes. This inhibition of protein synthesis disrupts cellular homeostasis and can have severe consequences for the target cells.
The toxic effects of Stx on target cells are multifaceted. The toxins induce inflammatory responses and cause severe cell damage in the intestine, kidneys, and brain. In humans, Shiga toxin-producing bacteria can lead to the development of hemolytic uremic syndrome (HUS), a life-threatening condition characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury. The precise mechanisms underlying the pathogenesis of HUS are complex and involve endothelial cell damage, platelet activation, and immune responses.
Stx can bind to cells expressing Gb3 receptors. The B subunit recognizes Gb3, while the A subunit is cytotoxic. Recombinant B subunits can be used to detect Gb3-expressing cells. Gb3 receptors are overexpressed in various types of tumor cells, including breast cancer, ovarian cancer, prostate cancer, and testicular cancer, as well as in tumor vasculature. In tumor imaging studies, radioactively labeled or fluorescence-labeled Shiga toxin B subunits have been used to detect Gb3-overexpressing tissues, even in regions where Gb3 receptors are normally absent. However, it is important to note that the B subunit may also bind to normal Gb3-repressing cells, leading to false signals and challenges in tumor detection when the tumor location is unknown.
Shiga toxin B subunits have shown promise in targeted therapy for Gb3-overexpressing tumors. They can be coupled with cytotoxic compounds for drug delivery to tumor cells. Studies have shown that in mouse models, intratumoral injection of Stx-1 induced apoptosis in tumor cells and vasculature without significant side effects. However, concerns about potential side effects similar to HUS exist. Drug conjugates face similar challenges, as cytotoxic components may harm normal cells. Strategies to mitigate side effects include using phototoxic drugs, drugs that preferentially kill tumor cells, and pro-drugs activated in the tumor's endoplasmic reticulum. Further research is needed to address toxicity, drug half-life, and immune responses to optimize the clinical application of Shiga toxins in tumor therapy.
References
| Target | Cat. No. | Product Name | Expression System | Tag/Conjugate | Application | |
| Shiga Toxins | DAGB118 | E. coli Shiga Toxin 2 | E. coli | Unconjugated | WB | Inquiry |
| DAGA-985 | Recombinant E.Coli O157:H7 Shiga Like Toxin-2 Subunit B [His] | E. coli | His | N/A | Inquiry | |
| DAGB117 | E. coli Shiga Toxin 1 | E. coli | Unconjugated | WB | Inquiry | |
| DAGA-984 | Recombinant shiga toxin-1 subunit B [His] | E. coli | His | N/A | Inquiry | |
| Shiga toxins | DAGA-878 | Recombinant shiga toxin 2 subunit b (aa 89,>98%) [His] | E. coli | His | N/A | Inquiry |
| DAGA-877 | Recombinant shiga toxin 1 subunit b (≥95%) [His] | E. coli | His | N/A | Inquiry | |
| GB3 | DAG-WT487 | GB3 [BSA] | N/A | BSA | N/A | Inquiry |
| DAG-WT488 | GB3 [OVA] | N/A | OVA | N/A | Inquiry | |
| S. dysenteriae | DAG-WT534 | Native Shigella dysenteriae | N/A | N/A | LF | Inquiry |
| E. coli | DAG1711 | Recombinant E. coli DnaJ Protein (a.a. 1-376) | E. coli | Unconjugated | SDS-PAGE | Inquiry |
| Target | Cat. No. | Product Name | Size | Species Reactivity | Application | Detection Sample | |
| Shiga Toxins | DEIASL162 | Shiga toxins ELISA Kit | 96T | Human | Qualitative | Fecal | Inquiry |
| E. coli | DEIA2348 | E. Coli Verotoxin (Fecal) ELISA Kit | 96T | Qualitative | stool supernatant | Inquiry | |
| DEIA2562 | E.coli Antigen In Food ELISA Kit | 96T | Quantitative | food | Inquiry | ||
| DEIA2437 | E.Coli O157 (Fecal) ELISA Kit | 96T | Qualitative | feces | Inquiry |
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