626th MEETING. SHEFFIELD 77s 4.6, respectively) and insensitivity to typical phosphodicstcrase inhibitors such as methylxanthines. Both enzymes were active in the absence of a metal cofactor but while the cyclic CMP phosphodiesterase was stimulated by Fe3+, Mg?+ and C 0 2 + and inhibited by Zn'+, Mn?+ and Ca?', the multifunctional enzyme differed in that it was stimulated by Mg'+, Ca2+ and Mn" and inhibited by Co?+ and Z n 2 + . Both enzymes were inhibited by phosphate and stimulated by cytosine and cytidine; the multifunctional enzyme, however. was insensitive to organic antioxidants, while the cyclic-CMP-specific phosphodiesterase was stimulated by cysteinc, glutathione and mercaptoethanol. The cyclic-CMP-specific enzyme was stimulated by testosterone and an endogenous protein and inhibited by calmodulin and a second endogenous protein; the multifunctional enzyme was insensitive to each of these factors.Of major significance is the response of thcse enzymes to the presence of other cyclic nucleotides during the hydrolysis of cyclic CMP. The multifunctional phosphodiesterase was competitively inhibited by 2', 3'and 3', 5'-cyclic nucleotides and deoxycyclic nucleotides; the cyclic-CMP-specific enzyme was also inhibited by these compounds, but it was less sensitive and inhibition varied from competitive, noncompetitive t o mixed inhibition dependent upon the nature of the nitrogenous base and the position of the cyclic phosphate ring. The K , of the cyclic-CMP-specific phosphodiesterase was an order of magnitude greater than that of the multifunctional phosphodiesterase, which is present at a higher concentration in most mammalian tissues. As V,,;,, for each enzyme is of the same order of magnitude, in thc absence of compartmentation effects and o f inhibition by other cyclic nucleotides, it can be deduced that the hydrolysis of cyclic CMP to CMP would be catalysed predominantly by the multifunctional phosphodiesterase. In the presence of high cellular concentrations of cyclic AMP and cyclic GMP, cyclic CMP hydrolysis would on the other hand be predominantly catalysed by the cyclic-CMP-specific phosphodiesterase, and sensitize the cyclic CMP turnover rate to changes in concentration of testosterone, calmodulin and the two endogenous proteinaceous effectors of cyclic CMP phosphodiesterase. The relative concentrations of cyclic AMP and cyclic GMP would thus appear t o be crucial factors in determination of the rate of breakdown of cyclic CMP.Although the cellular concentration of cyclic CMP is significantly lower than those of cyclic AMP and cyclic GMP, it is also feasible that cyclic CMP may exert an effect o n purine cyclic nucleotide hydrolysis by competing for the active site of the multifunctional phosphodiesterase. The effect of cyclic CMP on cyclic AMP and cyclic GMP hydrolysis may not be only confined to the activity of the multifunctional phosphodiesterase; analysis of a number of other phosphodiesterase activities from a variety of mammalian tissues has shown that cyclic CMP can act as a competitive, non-c...
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