Pharmacological toxins

Pharmacological toxins – Function by elevating or depressing normal cell functions but which do not result in death of their target cell.

Toxins that elevate cyclic AMP – Cholera toxin

These toxins raise the concentration of cyclic AMP (cAMP) without damaging the cell. The excess cAMP inhibits chemotaxis and phagocytosis, thus reducing their power to kill microorganisms. cAMP can be increased in several ways,
- some pathogens pour out cAMP themselves
- some secrete adenyl cyclase to make more cAMP from ATP
- secrete toxin that alters the activity of adenyl cyclase of host cells.

Cholera toxins (Best example)

It is an enterotoxin, a protein of mol.wt 90,000. Target tissue is the epithelium of the small intestine. It has separate A and B subunits
B component has specific affinity for the intestinal epithelial mucosa via gangliosiodic receptor.
A subunit has affinity to ADP-ribosylate of the target protein.
The target protein is part of a complex that makes cAMP. Synthesis of cAMP becomes unregulated and is made in large amount. This provokes loss of fluid and copious diarrhea which is the characteristic of Cholera.

Synthesis of cAMP

- The cyclic AMP is synthesized by the enzyme adenylate cyclase.
- It is composed of 3 proteins - Gs, R and cyclic itself.
- Gs protein is a GTP binding protein that has 2 conformational states.
- When it binds GTP, it stimulates adenylate cyclase to make cAMP.
- This effect is normally of short duration because Gs protein is also a GTPase that cleaves GTP to GDP.
- The activity of adenyl cyclase is thus determined by the balance of binding and hydrolysis of GTP by Gs protein.
- The balance of binding of GTP by Gs proteins is determined by R-protein which stimulates Gs.
- R-protein is a receptor for one of several hormones (adrenergic).
- Hence when R-protein binds one of these hormones, it interacts with Gs protein to increase its binding of GDP.
- Gs protein becomes active to stimulate adenyl cyclase.