![Shiga toxin (Stx) PDB 1r4q](https://upload.wikimedia.org/wikipedia/commons/a/a1/Shiga_toxin_%28Stx%29_PDB_1r4q.png)
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
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
of
lambdoid
The lambdoid suture (or lambdoidal suture) is a dense, fibrous connective tissue joint on the posterior aspect of the skull that connects the parietal bones with the occipital bone. It is continuous with the occipitomastoid suture.
Structure
Th ...
prophages.
The toxins are named after
Kiyoshi Shiga
was a Japanese physician and bacteriologist. He had a well-rounded education and career that led to many scientific discoveries. In 1897, Shiga was credited with the discovery and identification of the ''Shigella'' ''dysenteriae'' microorganism ...
, who first described the bacterial origin of
dysentery
Dysentery (UK pronunciation: , US: ), historically known as the bloody flux, is a type of gastroenteritis that results in bloody diarrhea. Other symptoms may include fever, abdominal pain, and a feeling of incomplete defecation. Complications ...
caused by ''
Shigella dysenteriae
''Shigella dysenteriae'' is a species of the rod-shaped bacterial genus ''Shigella''. ''Shigella'' species can cause shigellosis ( bacillary dysentery). Shigellae are Gram-negative, non-spore-forming, facultatively anaerobic, nonmotile bacteri ...
''.
Shiga-like toxin (SLT) is a historical term for similar or identical toxins produced by ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
''.
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.
Nomenclature
Microbiologists
A microbiologist (from Greek ) is a scientist who studies microscopic life forms and processes. This includes study of the growth, interactions and characteristics of microscopic organisms such as bacteria, algae, fungi, and some types of para ...
use many terms to describe Shiga toxin and differentiate more than one unique form. Many of these terms
are used interchangeably.
# Shiga toxin type 1 and type 2 (Stx-1 and 2) are the Shiga toxins produced by some'' E. coli'' strains. Stx-1 is identical to Stx of ''Shigella spp.'' or differs by only one amino acid.
Stx-2 shares 56%
sequence identity
In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Ali ...
with Stx-1.
# Cytotoxins – an archaic denotation for Stx – is used in a broad
sense
A sense is a biological system used by an organism for sensation, the process of gathering information about the world through the detection of stimuli. (For example, in the human body, the brain which is part of the central nervous system re ...
.
# Verocytotoxins/verotoxins – a seldom-used term for Stx – is from the hypersensitivity of
Vero cells
Vero may refer to: Geography
* Vero Beach, Florida, a city in the United States
* Vero, Corse-du-Sud, a commune of France in Corsica Other
* ''Véro'', a talk show on the Radio-Canada television network
* Vero (app), a social media company co-found ...
to Stx.
# The term Shiga-like toxins is another antiquated term which arose prior to the understanding that Shiga and Shiga-like toxins were identical.
History
The toxin is named after
Kiyoshi Shiga
was a Japanese physician and bacteriologist. He had a well-rounded education and career that led to many scientific discoveries. In 1897, Shiga was credited with the discovery and identification of the ''Shigella'' ''dysenteriae'' microorganism ...
, who discovered ''S. dysenteriae'' in 1897.
[ In 1977, researchers in ]Ottawa
Ottawa (, ; Canadian French: ) is the capital city of Canada. It is located at the confluence of the Ottawa River and the Rideau River in the southern portion of the province of Ontario. Ottawa borders Gatineau, Quebec, and forms the core ...
, Ontario
Ontario ( ; ) is one of the thirteen provinces and territories of Canada.Ontario is located in the geographic eastern half of Canada, but it has historically and politically been considered to be part of Central Canada. Located in Central C ...
discovered the Shiga toxin normally produced by ''Shigella dysenteriae
''Shigella dysenteriae'' is a species of the rod-shaped bacterial genus ''Shigella''. ''Shigella'' species can cause shigellosis ( bacillary dysentery). Shigellae are Gram-negative, non-spore-forming, facultatively anaerobic, nonmotile bacteri ...
'' in a line of ''E. coli''. The ''E. coli'' version of the toxin was named "verotoxin" because of its ability to kill ''Vero'' cells (African green monkey
''Chlorocebus'' is a genus of medium-sized primates from the family of Old World monkeys. Six species are currently recognized, although some people classify them all as a single species with numerous subspecies. Either way, they make up the ent ...
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
cells) in culture. Shortly after, the verotoxin was referred to as Shiga-like toxin because of its similarities to Shiga toxin.
It has been suggested by some researchers that the gene coding for Shiga-like toxin comes from a toxin-converting lambdoid bacteriophage, such as H-19B or 933W, inserted into the bacteria's chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
via transduction. Phylogenetic
In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...
studies of the diversity of ''E. coli'' suggest that it may have been relatively easy for Shiga toxin to transduce into certain strains of ''E. coli'', because ''Shigella
''Shigella'' is a genus of bacteria that is Gram-negative, facultative anaerobic, non-spore-forming, nonmotile, rod-shaped, and genetically closely related to '' E. coli''. The genus is named after Kiyoshi Shiga, who first discovered it in 1 ...
'' is itself a subgenus of ''Escherichia
''Escherichia'' () is a genus of Gram-negative, non- spore-forming, facultatively anaerobic, rod-shaped bacteria from the family Enterobacteriaceae. In those species which are inhabitants of the gastrointestinal tracts of warm-blooded animals, ...
''; in fact, some strains traditionally considered ''E. coli'' (including those that produce this toxin) in fact belong to this lineage. Being closer relatives of ''Shigella dysenteriae'' than of the typical
Typical may refer to:
* ''Typical'' (album), Peter Hammill
* "Typical" (song), song by MuteMath
*"Typical", song by Frazier Chorus from ''Sue'', 1987
*''Typical'', story collection by Padgett Powell, 1991
See also
*''Typical Rick
''Typical R ...
''E. coli'', it is not at all unusual that toxins similar to that of ''S. dysenteriae'' are produced by these strains. As microbiology advances, the historical variation in nomenclature (which arose because of gradually advancing science in multiple places) is increasingly giving way to recognizing all of these molecules as "versions of the same toxin" rather than "different toxins".
Transmission
The toxin requires highly specific receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s on the cells' surface in order to attach and enter the cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
; species
In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
such as cattle
Cattle (''Bos taurus'') are large, domesticated, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus ''Bos''. Adult females are referred to as cows and adult ma ...
, swine, and deer
Deer or true deer are hoofed ruminant mammals forming the family Cervidae. The two main groups of deer are the Cervinae, including the muntjac, the elk (wapiti), the red deer, and the fallow deer; and the Capreolinae, including the re ...
which do not carry these receptors may harbor toxigenic bacteria without any ill effect, shedding them in their feces, from where they may be spread to humans.
Clinical significance
Symptoms of Shiga toxin ingestion include abdominal pain as well as watery diarrhea. Severe life-threatening cases are characterized by hemorrhagic colitis (HC).
The toxin is associated with hemolytic-uremic syndrome. In contrast, ''Shigella'' species may also produce shigella enterotoxins, which are the cause of dysentery
Dysentery (UK pronunciation: , US: ), historically known as the bloody flux, is a type of gastroenteritis that results in bloody diarrhea. Other symptoms may include fever, abdominal pain, and a feeling of incomplete defecation. Complications ...
.
The toxin is effective against small blood vessels, such as found in the digestive tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
, the kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
, and lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side ...
, but not against large vessels such as the arteries
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
or major veins
Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated b ...
. A specific target for the toxin appears to be the vascular endothelium of the glomerulus
''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn".
''Glomerulus'' may refer to:
* the filter ...
. This is the filtering structure that is a key to the function of the kidney. Destroying these structures leads to kidney failure and the development of the often deadly and frequently debilitating hemolytic uremic syndrome. Food poisoning with Shiga toxin often also has effects on the lungs and the nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
.
Structure and mechanism
Mechanism
The B subunits of the toxin bind to a component of the cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
known as glycolipid globotriaosylceramide (Gb3). Binding of the subunit B to Gb3 causes induction of narrow tubular membrane invaginations, which drives formation of inward membrane tubules for the bacterial uptake into the cell. These tubules are essential for uptake into the host cell.
The Shiga toxin (a non-pore forming toxin) is transferred to the cytosol via Golgi network and endoplasmic reticulum (ER). From the Golgi toxin is trafficked to the ER.
Shiga toxins act to inhibit protein synthesis within target cells by a mechanism similar to that of the infamous plant toxin ricin. After entering a cell via a macropinosome
Macropinosomes are a type of cellular compartment that form as a result of macropinocytosis.
Formation
Macropinosomes have been described to form via a wave-like mechanism or via a tent-pole formation both of which processes require rapid polyme ...
, the payload (A subunit) cleaves a specific adenine nucleobase
Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...
from the 28S RNA of the 60S subunit of the ribosome, thereby halting protein synthesis. As they mainly act on the lining of the blood vessels, the vascular endothelium, a breakdown of the lining and hemorrhage eventually occurs. The first response is commonly a bloody diarrhea. This is because Shiga toxin is usually taken in with contaminated food or water
Water (chemical formula ) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living ...
.
The bacterial Shiga toxin can be used for targeted therapy of gastric cancer, because this tumor entity expresses the receptor of the Shiga toxin. For this purpose an unspecific chemotherapeutical is conjugated to the B-subunit to make it specific. In this way only the tumor cells, but not healthy cells, are destroyed during therapy.
Structure
The toxin has two subunits—designated A ( mol. wt. 32000 Da) and B (mol. wt. 7700 Da)—and is one of the AB5 toxins. The B subunit is a pentamer
A pentamer is an entity composed of five sub-units.
In chemistry, it applies to molecules made of five monomers.
In biochemistry, it applies to macromolecules, in particular to pentameric proteins, made of five proteic sub-units.
In microbiol ...
that binds to specific glycolipids on the host cell, specifically globotriaosylceramide
Globotriaosylceramide is a globoside. It is also known as CD77, Gb3, GL3, and ceramide trihexoside. It is one of the few clusters of differentiation that is not a protein.
It is formed by the alpha linkage of galactose to lactosylceramide catalyze ...
(Gb3). Following this, the A subunit is internalised and cleaved into two parts. The A1 component then binds to the ribosome, disrupting protein synthesis. Stx-2 has been found to be about 400 times more toxic (as quantified by LD50 in mice) than Stx-1.
Gb3 is, for unknown reasons, present in greater amounts in renal epithelial tissues, to which the renal toxicity of Shiga toxin may be attributed. Gb3 is also found in central nervous system neurons and endothelium, which may lead to neurotoxicity.
Stx-2 is also known to increase the expression of its receptor GB3 and cause neuronal dysfunctions.
See also
* 2011 German ''E. coli'' outbreak
* Cholera toxin
Cholera toxin (also known as choleragen and sometimes abbreviated to CTX, Ctx or CT) is AB5 multimeric protein complex secreted by the bacterium ''Vibrio cholerae''. CTX is responsible for the massive, watery diarrhea characteristic of cholera i ...
* Enterotoxin
An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines.
Enterotoxins are chromosomally encoded or plasmid encoded exotoxins that are produced and secreted from several bacterial organisms. They are heat la ...
* Pertussis toxin
Pertussis toxin (PT) is a protein-based AB5-type exotoxin produced by the bacterium ''Bordetella pertussis'', which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection. Rese ...
References
External links
* UniprotKB entries: stxA1 , stxB1 , stxA2 , stxB2
*
*
*
"Shigella"
in ''Todar's Online Textbook of Bacteriology''
"The So-called Chromosomal Verotoxin Genes are Actually Carried by Defective Prophages"
()
{{Toxins
AB5 toxins
Bacterial toxins
Biological toxin weapons
Ribosome-inactivating proteins