Question

Distinguish between the mechanism of cytotoxins and AB toxins and provide one example of each.

Answer 1

The mechanisms for cytotoxin-mediated toxicity include modulating the activity of membrane-bound enzymes, depolarizing excitable membranes of heart cells and of neurons, inhibiting platelet aggregation, inducing hemolysis and cytotoxicity, and bringing about cardiac arrest. It is widely accepted that most pathological activities of cytotoxins are based on their ability to bind to cell membranes leading to alterations in the organization and function of lipid bilayer.

Snake venom cytotoxins are highly basic amphipatic proteins and they constitute as much as 40–70% of cobra venom (Naja and Haemachatus). Snake envenomation due to Naja species is highly prevalent in Africa and mortality is often associated with the potent necrotic activity of Naja-derived cytotoxins. Pathologically, cytotoxins are responsible for severe myotoxicity, hemolysis, and necrosis in the affected human.

The AB toxins are two-component protein complexes secreted by a number of pathogenic bacteria. They can be classified as Type III toxins because they interfere with internal cell function. They are named AB toxins due to their components: the "A" component is usually the "active" portion, and the "B" component is usually the "binding" portion. The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit. These proteins consist of two independent polypeptides, which correspond to the A/B subunit moieties. The enzyme component (A) enters the cell through endosomes produced by the oligomeric binding/translocation protein (B), and prevents actin polymerisation through ADP-ribosylation of monomeric G-actin.

The Diphtheria toxin also is an AB toxin. It inhibits protein synthesis in the host cell through phosphorylation of the eukaryotic elongation factor 2, which is an essential component for protein synthesis. The exotoxin A of Pseudomonas aeruginosa is another example of an AB toxin that targets the eukaryotic elongation factor 2.

Examples of the "A" component of an AB toxin include Clostridium perfringens iota toxin Ia, C. botulinum C2 toxin CI, and Clostridium difficile ADP-ribosyltransferase.

Example of the B component of an AB toxin is Bacillus anthracis protective antigen (PA) protein, B. anthracis secretes three toxin factors: the protective antigen (PA); the oedema factor (EF); and the lethal factor (LF). Each is a thermolabile protein of ~80kDa. PA forms the "B" part of the exotoxin and allows passage of the "A" moiety (consisting of EF or LF) into target cells. PA protein forms the central part of the complete anthrax toxin, and translocates the A moiety into host cells after assembling as a heptamer in the membrane.