Shiga toxin: Difference between revisions
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<StructureSection load= | <StructureSection load='2xsc' size='350' side='right' scene='' caption='E. coli Shiga-like toxin 1 subunit B complex with Zn+2 (grey (PDB code [[2xsc]])'> | ||
==Introduction== | ==Introduction== | ||
'''Shiga Toxins''' are a family of [http://en.wikipedia.org/wiki/AB5_toxin AB5] toxins (Stx1 and Stx2) which cause [http://en.wikipedia.org/wiki/Dysentery dysentery], [http://en.wikipedia.org/wiki/Hemolytic-uremic_syndrome hemolytic-uremic syndrome], and potentially renal failure in humans. They are primarily secreted by Shiga toxin-encoding Escherichia coli (STEC), notably by the [http://en.wikipedia.org/wiki/0157:H7 0157:H7] strain<ref name=Wagner>PMID: 12010491</ref> and [http://en.wikipedia.org/wiki/Shigella_dysenteriae shigella dysentarie]. STECs are one of the major foodborne pathogens, affecting both developed and third-world countries. The stx gene is not endogenous to these strains, but is introduced through horizontal gene transfer from environmental prophages of the lambdoid bacteriophage family and incorporated into the E. Coli genome.<ref name=Wagner>PMID: 12010491</ref> Shiga Toxins are closely related to [[ricin]], which is structurally and mechanistically similar. Shiga toxin acts to inhibit protein synthesis in eukaryotic cells and is the main virulence factor of STEC. | '''Shiga Toxins''' are a family of [http://en.wikipedia.org/wiki/AB5_toxin AB5] toxins (Stx1 and Stx2) which cause [http://en.wikipedia.org/wiki/Dysentery dysentery], [http://en.wikipedia.org/wiki/Hemolytic-uremic_syndrome hemolytic-uremic syndrome], and potentially renal failure in humans. They are primarily secreted by Shiga toxin-encoding Escherichia coli (STEC), notably by the [http://en.wikipedia.org/wiki/0157:H7 0157:H7] strain<ref name=Wagner>PMID: 12010491</ref> and [http://en.wikipedia.org/wiki/Shigella_dysenteriae shigella dysentarie]. STECs are one of the major foodborne pathogens, affecting both developed and third-world countries. The stx gene is not endogenous to these strains, but is introduced through horizontal gene transfer from environmental prophages of the lambdoid bacteriophage family and incorporated into the E. Coli genome.<ref name=Wagner>PMID: 12010491</ref> Shiga Toxins are closely related to [[ricin]], which is structurally and mechanistically similar. Shiga toxin acts to inhibit protein synthesis in eukaryotic cells and is the main virulence factor of STEC. For toxins in Proteopedia see [[Toxins]]. | ||
==Human Interaction== | ==Human Interaction== | ||
0157:H7 STECs are spread to humans through a fecal-oral mechanism, primarily from ingestion of food contaminated with fecal material. Cattle, goats, and sheep are the primary reservoir of STECs and their close proximity to food sources as well as the use of animal feces for fertilizer makes them the main route of contamination.<ref name=Herold>PMID: 15493821</ref> Inadequate sanitation and contamination of meat during slaughter can both lead to STEC contaminated food at the market. Once ingested the STEC can survive the high acid environment of the stomach and progress to the gut where they attach firmly to gut mucosa via the [http://en.wikipedia.org/wiki/Intimin intimin adhesin protein].<ref name=Russel>PMID: 11321582</ref> Secreted Stx then either attacks gut epithelia or passes into the bloodstream where it can damage kidney and brain tissue. | 0157:H7 STECs are spread to humans through a fecal-oral mechanism, primarily from ingestion of food contaminated with fecal material. Cattle, goats, and sheep are the primary reservoir of STECs and their close proximity to food sources as well as the use of animal feces for fertilizer makes them the main route of contamination.<ref name=Herold>PMID: 15493821</ref> These animals can house STEC's without effect due to a lack of Stx surface receptors.<ref name=Asakura>PMID: 11561972</ref> Inadequate sanitation and contamination of meat during slaughter can both lead to STEC contaminated food at the market. Once ingested the STEC can survive the high acid environment of the stomach and progress to the gut where they attach firmly to gut mucosa via the [http://en.wikipedia.org/wiki/Intimin intimin adhesin protein].<ref name=Russel>PMID: 11321582</ref> Secreted Stx then either attacks gut epithelia or passes into the bloodstream where it can damage kidney and brain tissue. | ||
==Treatments== | |||
Treatment with antibiotics is contraindicated as antibiotic treatment has been demonstrated to increase Stx production up to one hundred fold.<ref name=Herold>PMID: 15493821</ref> This results from the link between Stx production (and phage induction) to the [http://en.wikipedia.org/wiki/SOS_response SOS response pathway].<ref name=Herold>PMID: 15493821</ref> In the event of renal failure kidney dialysis may be employed. A number of potential treatments are under development including B subunit inhibitors, polysaccharides that promote macrophage uptake of Stx, blocking of the Gb<sub>3</sub> membrane receptor, and inhibition of [http://en.wikipedia.org/wiki/Retrograde_transport#Retrograde_transport retrograde transport].<ref name=Nishikiwa>PMID: 21644029</ref> | Treatment with antibiotics is contraindicated as antibiotic treatment has been demonstrated to increase Stx production up to one hundred fold.<ref name=Herold>PMID: 15493821</ref> This results from the link between Stx production (and phage induction) to the [http://en.wikipedia.org/wiki/SOS_response SOS response pathway].<ref name=Herold>PMID: 15493821</ref> In the event of renal failure kidney dialysis may be employed. A number of potential treatments are under development including B subunit inhibitors, polysaccharides that promote macrophage uptake of Stx, blocking of the Gb<sub>3</sub> membrane receptor, and inhibition of [http://en.wikipedia.org/wiki/Retrograde_transport#Retrograde_transport retrograde transport].<ref name=Nishikiwa>PMID: 21644029</ref> | ||
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Shiga Toxin consists consists of an AB<sub>5</sub> hexamer.<ref name=Fraser>PMID: 7656009</ref> The | Shiga Toxin consists consists of an AB<sub>5</sub> hexamer.<ref name=Fraser>PMID: 7656009</ref> The | ||
<scene name='Shiga_toxin_1/Subunits/1'>5 subunit B pentamer interacts with the A subunit</scene> via a <scene name='Shiga_toxin_1/A-b_helixes/1'>C-terminal helix of hydrophobic subunits packed antiparallel to 5 B helixes</scene> and | <scene name='Shiga_toxin_1/Subunits/1'>5 subunit B pentamer interacts with the A subunit</scene> via a <scene name='Shiga_toxin_1/A-b_helixes/1'>C-terminal helix of hydrophobic subunits packed antiparallel to 5 B helixes</scene> and | ||
<scene name='Shiga_toxin_1/Beta_sheet/1'>4 antiparallel beta sheets</scene>.<ref name=Fraser>PMID: 7656009</ref>. The <scene name='Shiga_toxin_1/Active_site_zoomed_out_a-b/1'>glycosidase active site</scene> is located on the A subunit, but is blocked by the B subunit until | <scene name='Shiga_toxin_1/Beta_sheet/1'>4 antiparallel beta sheets</scene>.<ref name=Fraser>PMID: 7656009</ref>. The <scene name='Shiga_toxin_1/Active_site_zoomed_out_a-b/1'>glycosidase active site</scene> is located on the A subunit, but is blocked by the B subunit until the <scene name='Shiga_toxin_1/Disulphide_bond/1'>disulphide bond between cys242 and cys261</scene> is cleaved releasing an active A subunit into the target cell.<ref name=Fraser>PMID: 7656009</ref> | ||
==Function== | ==Function== | ||
Shiga Toxin acts as an N-glycosidase, removing an adenine from the | Shiga Toxin acts as an N-glycosidase, removing an adenine from the 28S ribosomal rRNA of a target cell which leads to inhibition of protein elongation and ultimately cellular apoptosis.<ref name=Di>PMID: 21184769</ref> The B subunit is necessary for binding to globo series glycolipid globotriaosylceramide (Gb<sub>3</sub>), a eukaryotic membrane receptor, where it is then endocytosed and proteolytically cleaved into an active A subunit and a B subunit.<ref name=Lenz>PMID: 2170899</ref> The B subunit is not active in the depurination of of 28S rRNA, but is essential for GB<sub>3</sub> binding and therefore essential for toxicity. Once in the cytosol the A subunit is free to interact with and inactivate 28S rRNA. On the A subunit <scene name='Shiga_toxin_1/Active_site_zoomed_in/1'>Tyr77, Tyr114, Glu167, Arg170, and Trp203</scene> are all essential in glycosidic activity.<ref name=Di>PMID: 21184769</ref> This mechanism (B subunit binding to globotriaosylceramide and A subunit depurinating 28S rRNA) is conserved amongst the Stx family as well as the ricin toxin. | ||
==3D structures of shiga toxin== | |||
[[Shiga toxin 3D structures]] | |||
[[ | |||
</StructureSection> | |||
==References== | ==References== | ||
{{Reflist}} | {{Reflist}} | ||
[[Category:Topic Page]] | |||