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.
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002462:Cell Membrane / Q000201:enzymology; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000031:analogs & derivatives*; D008024:Ligands / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008223:Lymphoma / Q000201:enzymology; D051379:Mice; D009374:Neoplasms, Experimental / Q000201:enzymology; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000187:drug effects*; D011983:Receptors, Purinergic
D000067956:Adenylyl Cyclase Inhibitors; D003839:Deoxyadenosines; D008024:Ligands; D011956:Receptors, Cell Surface; D011983:Receptors, Purinergic; D016048:Dideoxyadenosine; C021008:2',5'-dideoxyadenosine; D000262:Adenylyl Cyclases