42] Toxin ADP-ribosyltransferases that act on adenylate cyclase systems

Abstract

This chapter describes toxin ADP-ribosyltransferases that act on adenylate cyclase systems. cAMP plays a significant role in control of metabolism and function of many cells. The activity of adenylate cyclase, the enzyme responsible for cAMP synthesis, is regulated by both inhibitory and stimulatory molecules. Three bacterial toxins are known to exert their effects on cells through activation of the adenylate cyclase system. Choleragen and E. coli heat-labile enterotoxin, toxins involved in the pathogenesis of cholera and traveler's diarrhea, respectively, enhance cyclase activity by acting on the stimulatory arm of the system. Pertussis toxin, which may play a role in whooping cough, appears to increasecyclase activity by preventing the action of inhibitory ligands. An adenylate cyclase system generally consists of at least five components. The catalytic unit (C) is responsible for the conversion of ATP to cAMP. Stimulatory and inhibitory ligands act by binding to gonist-specific cell surface receptors. Stimulatory (Rs) and inhibitory (Ri) receptors are coupled to the catalytic unit through different GTP-binding regulatory proteins termed Gs and Gi, respectively. Demonstration of hormonal stimulation or inhibition of adenylate cyclase activity requires agonist, its specific receptor, the appropriate GTP-binding protein (Gs or Gi) and GTP. Toxin action on cells involves multiple steps from initial binding to the membrane through activation of adenylate cyclase and finally alterations in metabolism or function.