Conformational basis for the activation of adenylate cyclase by adenosine

Abstract

The ability of adenosine to stimulate adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and increase cyclic[c]AMP levels has important biochemical consequences. These include suppression of immune responses and cardiovascular effects. Recent investigations involving the ability of adenosine and adenosine analogs to stimulate adenylate cyclase provided experimental data that appear to be correlated with the ability of adenosine and analogs of adenosine to exist in the glycosidic high anti conformation. 9-.beta.-D-Arabinofuranosyladenine, which is not stable in the high anti conformation, is inactive as a stimulator of adenylate cyclase. 2''-Deoxyadenosine is not stable in the high anti conformation, but its instability may be significantly decreased by intramolecular adjustments promoted by receptor or active site interactions. 2''-Deoxyadenosine does not activate adenylate cyclase in lymphocytes when ATP is the substrate but is able to activate adenylate cyclase when 2-fluoro ATP is the substrate. The inability of certain analogs of adenosine, with bulky groups substituted for H at the 8 position of the adenine base, to activate adenylate cyclase and increase lymphocyte or cardiac cell cAMP levels is consistent with the designation of the high anti conformation as being the conformation required for activation of adenylate cyclase. An understanding of the glycosidic conformation required by the extracellular adenosine receptor of the adenosine molecule provides the basis for designing nucleoside analogs of adenosine that will exert a desired effect on cAMP levels. Avoidance of unwanted immunosuppressive or cardiotoxic effects can be arranged by structural changes that prohibit the high anti conformation. There are several aspects to the toxicity associated with an excess of adenosine. The enzymes adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) and adenosine kinase (ATP:adenosine-5''-phosphotransferase, EC 2.7.1.20) compete for adenosine. At higher concetrations of adenosine, adenosine deaminase dominates and protects the body from the effects of an excess of adenosine.