Clostridium perfringens alpha toxin
Encyclopedia
Clostridium perfringens alpha toxin is a toxin
produced by the bacterium Clostridium perfringens
(C. perfringens) and is responsible for gas gangrene
and myonecrosis in infected
tissue
s. The toxin also possesses hemolytic activity.
; the bacterium is unable to cause disease without this toxin. Further, vaccination against the alpha toxin toxoid protects mice against C. perfringens gas gangrene
. As a result, knowledge about the function of this particular protein greatly aids understanding of myonecrosis.
, C. bifermentans, and Listeria monocytogenes. The C terminal domain shows similarity with non-bacterial enzymes such as pancreatic lipase
, soybean lipoxygenase, and synaptotagmin
I.
The alpha toxin is a zinc metallophospholipase requiring zinc
for activation. First, the toxin binds to a binding site on the cell surface. The C-terminal C2-like
PLAT domain
binds calcium
and allows the toxin to bind to the phospholipid
head-groups on the cell surface. The C-terminal domain enters the phospholipid bilayer. The N-terminal domain has phospholipase
activity. This property allows hydrolysis
of phospholipids such as phosphatidyl choline, mimicking endogenous phospholipase C
. The hydrolysis
of phosphatidyl choline produces diacylglycerol
which activates a variety of second messenger pathways. The end result includes activation of arachidonic acid
pathway and production of thromboxane A2
, production of IL-8
, platelet-activating factor
, and several intercellular adhesion molecules. These actions combine to cause edema
due to increased vascular permeability.
Toxin
A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...
produced by the bacterium Clostridium perfringens
Clostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...
(C. perfringens) and is responsible for gas gangrene
Gas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
and myonecrosis in infected
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
s. The toxin also possesses hemolytic activity.
Clinical significance
This toxin has been shown to be the key virulence factor in infection with C. perfringensClostridium perfringens
Clostridium perfringens is a Gram-positive, rod-shaped, anaerobic, spore-forming bacterium of the genus Clostridium. C. perfringens is ever present in nature and can be found as a normal component of decaying vegetation, marine sediment, the intestinal tract of humans and other vertebrates,...
; the bacterium is unable to cause disease without this toxin. Further, vaccination against the alpha toxin toxoid protects mice against C. perfringens gas gangrene
Gas gangrene
Gas gangrene is a bacterial infection that produces gas tissues in gangrene. It is a deadly form of gangrene usually caused by Clostridium perfringens bacteria. It is a medical emergency....
. As a result, knowledge about the function of this particular protein greatly aids understanding of myonecrosis.
Structure and homology
The alpha toxin has remarkable similarity to toxins produced by other bacteria as well as natural enzymes. There is significant homology with phospholipase C enzymes from Bacillus cereusBacillus cereus
Bacillus cereus is an endemic, soil-dwelling, Gram-positive, rod-shaped, beta hemolytic bacterium. Some strains are harmful to humans and cause foodborne illness, while other strains can be beneficial as probiotics for animals...
, C. bifermentans, and Listeria monocytogenes. The C terminal domain shows similarity with non-bacterial enzymes such as pancreatic lipase
Pancreatic lipase
Pancreatic lipase, also known as pancreatic triacylglycerol lipase, is secreted from the pancreas, and is the primary lipase that hydrolyzes dietary fat molecules in the human digestive system, converting triglyceride substrates found in ingested oils to monoglycerides and free fatty acids.Bile...
, soybean lipoxygenase, and synaptotagmin
Synaptotagmin
Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...
I.
The alpha toxin is a zinc metallophospholipase requiring zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
for activation. First, the toxin binds to a binding site on the cell surface. The C-terminal C2-like
C2 domain
A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. It is a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by the first and final loops of the domain, on the membrane binding face.-Coupling...
PLAT domain
PLAT domain
PLAT domain is found in a variety of membrane or lipid associated proteins. It is called the PLAT domain or LH2 domain. The known structure...
binds calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and allows the toxin to bind to the phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
head-groups on the cell surface. The C-terminal domain enters the phospholipid bilayer. The N-terminal domain has phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
activity. This property allows hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of phospholipids such as phosphatidyl choline, mimicking endogenous phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
. The hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of phosphatidyl choline produces diacylglycerol
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
which activates a variety of second messenger pathways. The end result includes activation of arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
pathway and production of thromboxane A2
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....
, production of IL-8
IL-8
IL-8 can refer to:* Interleukin 8, a chemokine of the immune system* Illinois' 8th congressional district* Illinois Route 8...
, platelet-activating factor
Platelet-activating factor
Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC is a potent phospholipid activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis...
, and several intercellular adhesion molecules. These actions combine to cause edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
due to increased vascular permeability.