Activation and dissociation of adenosine 3′,5′-monophosphate-dependent and guanosine 3′,5′-monophosphate-dependent protein kinases by various cyclic nucleotide analogs

Abstract

The effects of various analogs of adenosine 3′,5′-monophosphate (cyclic AMP), guanosine 3′,5′-monophosphate (cyclic GMP), and inosine 3′,5′-monophosphate (cyclic IMP) in stimulating and dissociating cyclic AMP-dependent and cyclic GMP-dependent classes of protein kinases were examined. With the possible exceptions of the dibutyryl derivative of cyclic GMP and the cyclothiophosphate analog of cyclic AMP, all compounds tested were capable of maximally stimulating both classes of protein kinases, and some analogs were more reactive than the parent compounds. The effectiveness of these compounds in activating these protein kinases paralleled their ability to cause the dissociation of the enzymes into subunits. Some compounds, notably the 8-thio and 8-methylthio analogs of cyclic AMP, which were at least as reactive as cyclic AMP in dissociating and stimulating the cyclic AMP-dependent enzyme, did not compete, but unexpectedly cooperatively enhanced the binding of the radioactive cyclic AMP to this enzyme, suggesting that these sulfur-containing analogs may interact with specific sites on the enzyme different from cyclic AMP. Many of the cyclic AMP analogs, like cyclic GMP, supported the stimulatory action of the protein kinase modulator on arginine-rich histone phosphorylation catalyzed by cyclic GMP-dependent protein kinase. The modulator, however, inhibited the cyclic AMP-dependent class of protein kinase activated by any of the cyclic nucleotides and analogs under the same assay conditions.