Regulation of the catalytic component of adenylate cyclase. Potentiative interaction of stimulatory ligands and 2',5'-dideoxyadenosine

Both adenosine and the P site agent 2',5'-dideoxyadenosine (DDA) reversibly inhibit adenylate cyclase activity in two different preparations of the enzyme that lack the stimulatory guanine nucleotide-binding protein, G/F: plasma membranes from the cyc^- variant of S49 lymphoma cells and the resolved catalytic component (C) from rabbit liver. P site agents do not compete with any of the activators of C (Mn²⁺, G/F, forskolin), nor do they diminish the potency of any activator of C. Rather, activation of C increases the effectiveness of P site agents and causes up to a 10,000-fold increase in the potency of DDA. The ability of G/F or forskolin to potentiate P site inhibition is also noted at concentrations much lower than those required for the stimulation of adenylate cyclase activity. These data are inconsistent with a simple two-state allosteric model for the regulation of the activity of C and demand the postulation of either a distinct, inhibited conformation of the enzyme or the existence of a dead-end complex with adenosine bound to the catalytic site.