''Clostridium perfringens'' alpha toxin is a

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...

produced by the

bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

Clostridium perfringens ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, rod-shaped, anaerobic, spore-forming pathogenic bacterium of the genus '' Clostridium''. ''C. perfringens'' is ever-present in nature an ...

'' (''C. perfringens'') and is responsible for

gas gangrene Gas gangrene (also known as clostridial myonecrosis and myonecrosis) is a bacterial infection that produces tissue gas in gangrene. This deadly form of gangrene usually is caused by '' Clostridium perfringens'' bacteria. About 1,000 cases of gas ...

and

myonecrosis Gas gangrene (also known as clostridial myonecrosis and myonecrosis) is a bacterial infection that produces tissue gas in gangrene. This deadly form of gangrene usually is caused by ''Clostridium perfringens'' bacteria. About 1,000 cases of gas g ...

in infected tissues. The toxin also possesses

hemolytic Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo o ...

activity.

Clinical significance

This toxin has been shown to be the key virulence factor in infection with ''

C. perfringens ''Clostridium perfringens'' (formerly known as ''C. William H. Welch, welchii'', or ''Bacillus welchii'') is a Gram-positive, rod-shaped, anaerobic bacterium, anaerobic, Endospore, spore-forming pathogenic bacterium of the genus ''Clostridium''. ...

''; the bacterium is unable to cause disease without this toxin. Further, vaccination against the alpha toxin toxoid protects mice against ''C. perfringens''

. As a result, knowledge about the function of this particular protein greatly aids understanding of

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 Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...

enzymes from ''

Bacillus cereus ''Bacillus cereus'' is a Gram-positive rod-shaped bacterium commonly found in soil, food, and marine sponges. The specific name, ''cereus'', meaning "waxy" in Latin, refers to the appearance of colonies grown on blood agar. Some strains are ha ...

'', ''C. bifermentans'', and ''

Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the host' ...

''. The C terminal domain shows similarity with non-bacterial enzymes such as

pancreatic lipase Triglyceride lipases () are a family of lipolytic enzymes that hydrolyse ester linkages of triglycerides. Lipases are widely distributed in animals, plants and prokaryotes. At least three tissue-specific isozymes exist in higher vertebrates, p ...

, soybean lipoxygenase, and

synaptotagmin Synaptotagmins (SYTs) constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region (TMR), a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 17 isoforms in the mammalian s ...

I. The alpha toxin is a zinc metallophospholipase, requiring

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

for activation. First, the toxin binds to a binding site on the cell surface. The C-terminal C2-like PLAT domain binds

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

and allows the toxin to bind to the

phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

head-groups on the cell surface. The C-terminal domain enters the

phospholipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...

. The N-terminal domain has

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...

activity. This property allows

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of phospholipids such as

phosphatidyl choline Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soyb ...

, mimicking endogenous

. The

of phosphatidyl choline produces

diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...

, which activates a variety of

second messenger Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...

pathways. The end-result includes activation of

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...

pathway and production of thromboxane A₂, production of IL-8, platelet-activating factor, and several intercellular adhesion molecules. These actions combine to cause

edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

due to increased vascular permeability.

References

Bacterial toxins Peripheral membrane proteins Clostridiaceae Gas gangrene {{portal bar, Biology

Clinical significance

Structure and homology

See also

References