Editing Enterotoxin

{{Short description|Toxin from a microorganism affecting the intestines}}
{{Infobox protein family
| Symbol = Stap_Strp_tox_C
| Name = Staph/Strep enterotoxin, C terminal
| image = PDB 1uns EBI.jpg
| width = 
| caption = identification of a secondary zinc-binding site in staphylococcal enterotoxin c2: implications for superantigen recognition
| Pfam = PF02876
| Pfam_clan = CL0386 
| InterPro = IPR006123
| SMART = 
| PROSITE = PDOC00250
| MEROPS = 
| SCOP = 1se3
| TCDB = 
| OPM family = 364
| OPM protein = 1dyq
| CAZy = 
| CDD = 
}}

An '''enterotoxin''' is a [[protein]] [[exotoxin]] released by a [[microorganism]] that targets the [[intestines]].<ref>{{DorlandsDict|three/000035767|enterotoxin}}</ref> They can be chromosomally or plasmid encoded.<ref>Carlton Gyles, Magdalene So, Stanley Falkow, Journal of Infectious Diseases (1974)   130  (1):  40-49.</ref> They are heat [[Lability#Biology|labile]] (> 60 °C), of low molecular weight and water-soluble. Enterotoxins are frequently [[cytotoxic]] and kill cells by altering the apical membrane [[Semipermeable membrane|permeability]] of the mucosal ([[epithelial]]) cells of the intestinal wall. They are mostly [[pore-forming toxin]]s (mostly chloride pores), secreted by bacteria, that assemble to form pores in [[cell membranes]]. This causes the cells to die.

== Clinical significance ==

Enterotoxins have a particularly marked effect upon the [[gastrointestinal tract]], causing [[traveler's diarrhea]] and food poisoning. The action of enterotoxins leads to increased [[chloride ion]] permeability of the [[apical membrane]] of intestinal mucosal cells. These membrane pores are activated either by increased [[Cyclic adenosine monophosphate|cAMP]] or by increased calcium ion concentration intracellularly. The pore formation has a direct effect on the [[osmolarity]] of the [[lumen (anatomy)|luminal]] contents of the intestines. Increased chloride permeability leads to leakage into the lumen followed by sodium and water movement. This leads to a [[secretory diarrhea]] within a few hours of ingesting enterotoxin. Several microbial organisms contain the necessary enterotoxin to create such an effect, such as ''Staphylococcus aureus'' and ''E. coli''.<ref name=Hornby/>

The drug [[linaclotide]], used to treat some forms of constipation, is based on the mechanism of enterotoxins.<ref name=Hornby>{{cite journal|last1=Hornby|first1=PJ|title=Drug discovery approaches to irritable bowel syndrome.|journal=Expert Opinion on Drug Discovery|date=2015|volume=10|issue=8|pages=809–24|doi=10.1517/17460441.2015.1049528|pmid=26193876|s2cid=207494271}}</ref>

== Classification and 3D structures ==

=== Bacterial ===

Enterotoxins can be formed by the bacterial pathogens ''Staphylococcus aureus'' and ''Bacillus cereus'' and can cause [[Staphylococcal food poisoning|Staphylococcal Food Poisoning]] and ''Bacillus cereus'' diarrheal disease, respectively. Staphylococcal enterotoxins and streptococcal [[exotoxin]]s constitute a family of biologically and structurally related pyrogenic [[superantigen]]s.<ref>{{Cite journal|last1=Dinges|first1=M. M.|last2=Orwin|first2=P. M.|last3=Schlievert|first3=P. M.|date=2000|title=Exotoxins of Staphylococcus aureus|journal=Clinical Microbiology Reviews|volume=13|issue=1|pages=16–34, table of contents|issn=0893-8512|pmid=10627489|pmc=88931|doi=10.1128/CMR.13.1.16}}</ref> 25 staphylococcal enterotoxins (SEs), mainly produced by ''[[Staphylococcus aureus]]'', have been identified to date and named alphabetically (SEA – SEZ).<ref>{{cite journal |last1=Etter |first1=Danai |last2=Schelin |first2=Jenny |last3=Schuppler |first3=Markus |last4=Johler |first4=Sophia |title=Staphylococcal Enterotoxin C—An Update on SEC Variants, Their Structure and Properties, and Their Role in Foodborne Intoxications |journal=Toxins |date=2020-09-10 |volume=12 |issue=9 |pages=584 |doi=10.3390/toxins12090584 |pmid=32927913 | pmc=7551944 |hdl=20.500.11850/441345 |hdl-access=free |doi-access=free }}</ref> It has been suggested that ''staphylococci'' other than ''S. aureus'' can contribute to Staphylococcal Food Poisoning by forming enterotoxins.<ref>{{Cite journal|last1=Fetsch|first1=Alexandra|last2=Johler|first2=Sophia|date=2018-04-27|title=Staphylococcus aureus as a Foodborne Pathogen|journal=Current Clinical Microbiology Reports|language=en|volume=5|issue=2|pages=88–96|doi=10.1007/s40588-018-0094-x|s2cid=13668423|issn=2196-5471}}</ref> Streptococcal exotoxins are produced by ''[[Streptococcus pyogenes]]''.<ref name="pmid2679358">{{cite journal | author = Iandolo JJ | title = Genetic analysis of extracellular toxins of Staphylococcus aureus | journal = Annu. Rev. Microbiol. | volume = 43 | pages = 375–402 | year = 1989 | pmid = 2679358 | doi = 10.1146/annurev.mi.43.100189.002111 }}</ref><ref name="pmid2185544">{{cite journal |vauthors=Marrack P, Kappler J | title = The staphylococcal enterotoxins and their relatives | journal = Science | volume = 248 | issue = 4956 | pages = 705–11 |date=May 1990 | pmid = 2185544 | doi = 10.1126/science.2185544| bibcode = 1990Sci...248..705M | s2cid = 33752378 }}</ref> These toxins share the ability to [[Molecular binding|bind]] to the [[major histocompatibility complex]] proteins of their hosts. A more distant relative of the family is the ''S. aureus ''[[toxic]] shock syndrome toxin, which shares only a low level of [[sequence (biology)|sequence]] similarity with this group.

All of these toxins share a similar two-domain [[protein folding|fold]] (N and [[C-terminal domain]]s) with a long [[alpha-helix]] in the middle of the molecule, a characteristic [[beta-barrel]] known as the "oligosaccharide/oligonucleotide fold" at the N-terminal [[Domain (biology)|domain]] and a beta-grasp [[protein motif|motif]] at the C-terminal domain. An example is [[Staphylococcal Enterotoxin B|staphylococcal enterotoxin B]]. Each superantigen possesses slightly different [[binding (molecular)|binding]] mode(s) when it [[protein–protein interaction|interact]]s with [[MHC class II]] molecules or the [[T-cell receptor]].<ref name="pmid9514739">{{cite journal |vauthors=Papageorgiou AC, Tranter HS, Acharya KR | title = Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors | journal = J. Mol. Biol. | volume = 277 | issue = 1 | pages = 61–79 |date=March 1998 | pmid = 9514739 | doi = 10.1006/jmbi.1997.1577 }}</ref>

The beta-grasp domain has some [[secondary structure|structural]] similarities to the beta-grasp [[sequence motif|motif]] present in immunoglobulin-binding domains, [[ubiquitin]], 2Fe-2 S [[ferredoxin]] and [[Translation (genetics)|translation]] [[Eukaryotic initiation factor|initiation factor]] 3 as identified by the [[SCOP database]].

* ''[[Clostridioides difficile (bacteria)|Clostridioides difficile]]''
* ''[[Clostridium perfringens]]'' ([[Clostridium enterotoxin]])<ref name="pmid9334247">{{cite journal |vauthors=Katahira J, Sugiyama H, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N |title=Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo |journal=The Journal of Biological Chemistry |volume=272 |issue=42 |pages=26652–8 |date=October 1997 |pmid=9334247 |doi= 10.1074/jbc.272.42.26652|doi-access=free }}</ref>
* ''[[Vibrio cholerae]]'' ([[Cholera toxin]])<ref name="Mesh">{{MeshName|Enterotoxins}}</ref>
* ''[[Staphylococcus aureus]]'' ([[Staphylococcal enterotoxin B]])<ref name=eMedicine830715>{{EMedicine|article|830715|CBRNE - Staphylococcal Enterotoxin B}}</ref>
* ''[[Yersinia enterocolitica]]''
* ''[[Shigella dysenteriae]]'' ([[Shiga toxin]])<ref name="Mesh"/>

=== Viral ===

Viruses in the families ''[[Reoviridae]]'', ''[[Caliciviridae]]'', and ''[[Astroviridae]]'' are responsible for a huge percentage of gastrointestinal disease worldwide. [[Rotavirus]]es (of ''Reoviridae'') have been found to contain an '''enterotoxin''' which plays a role in viral pathogenesis. '''NSP4''', is a protein that is made during the intracellular phase of the virion's life cycle and is known to have a primary function in intracellular virion maturation.<ref>{{cite journal |last1=Crawford |first1=Sue E. |last2=Ramani |first2=Sasirekha |last3=Tate |first3=Jacqueline E. |last4=Parashar |first4=Umesh D. |last5=Svensson |first5=Lennart |last6=Hagbom |first6=Marie |last7=Franco |first7=Manuel A. |last8=Greenberg |first8=Harry B. |last9=O'Ryan |first9=Miguel |last10=Kang |first10=Gagandeep |last11=Desselberger |first11=Ulrich |last12=Estes |first12=Mary K. |title=Rotavirus infection |journal=Nature Reviews Disease Primers |date=9 November 2017 |volume=3 |issue=1 |page=17083 |doi=10.1038/nrdp.2017.83 |pmid=29119972 |pmc=5858916 }}</ref> However, when NSP4 from group A Rotaviruses was purified (4 alleles tested), concentrated, and injected into a mouse model, diarrheal disease mimicking that caused by Rotavirus infection commenced.<ref>{{cite journal |last1=Horie |first1=Y. |last2=Nakagomi |first2=O. |last3=Koshimura |first3=Y. |last4=Nakagomi |first4=T. |last5=Suzuki |first5=Y. |last6=Oka |first6=T. |last7=Sasaki |first7=S. |last8=Matsuda |first8=Y. |last9=Watanabe |first9=S. |title=Diarrhea Induction by Rotavirus NSP4 in the Homologous Mouse Model System |journal=Virology |date=September 1999 |volume=262 |issue=2 |pages=398–407 |doi=10.1006/viro.1999.9912 |pmid=10502518 |doi-access=free }}</ref> A putative mode of toxicity is that NSP4 activates a signal transduction pathway that ultimately results in an increased cellular concentration of calcium and subsequent chloride secretion from the cell.<ref>{{cite journal |last1=Zhang |first1=Mingdong |last2=Zeng |first2=Carl Q.-Y. |last3=Morris |first3=Andrew P. |last4=Estes |first4=Mary K. |title=A Functional NSP4 Enterotoxin Peptide Secreted from Rotavirus-Infected Cells |journal=Journal of Virology |date=15 December 2000 |volume=74 |issue=24 |pages=11663–11670 |doi=10.1128/JVI.74.24.11663-11670.2000 |pmid=11090165 |pmc=112448 }}</ref> Secretion of ions from villi lining the gut alter normal osmotic pressures and prevent uptake of water, eventually causing diarrhea.

* ''[[Rotavirus]]'' ([[NSP4 (rotavirus)|NSP4]])

== See also ==
* [[Endotoxin]]
* [[Exotoxin]]

== References ==
{{Reflist}}

== External links ==
* {{cite journal | journal = Public Health Rep | date = Mar 1959 | volume = 74 | issue = 3 | pages = 265–270 | pmc = 1929208 | title = Two poisoning outbreaks in Puerto Rico from salt preserved codfish |author1=Alfonse T. Masi |author2=Rafael A. Timothee |author3=Rolando Armijo |author4=Darwin Alonso |author5=Luis E. Mainardi | doi=10.2307/4590423 | pmid=13634314| jstor = 4590423 }}

{{Toxins}}

{{InterPro content|IPR006123}}

[[Category:Toxins by organ system affected]]
[[Category:Peripheral membrane proteins]]
[[Category:Protein families]]