Adenosine 3´, 5´-Monophosphate: On Its Mechanism of Action

ADENOSINE 3',5'-MONOPHOSPhA TE: ON ITS MECHANISM OF ACTION* WAI YIU CHEUNG1! It is well established that cyclic AMP mediates the actions of a variety of hormones. Various aspects of the nucleotide have been described in recent reviews and monographs [1-4]. Most of the work on cyclic AMP concerns its metabolism and function, while relatively little is known of the mechanism by which it acts. This paper analyzes some of the reactions or processes known to be affected by cyclic AMP and searches for a common denominator which may shed light on its mechanism of action. The approach is analytical, and work from various laboratories is examined for clues. In formulating a unifying hypothesis it is important to recognize some of the basic attributes of cyclic AMP. The cyclic phosphate ring is constrained, which may account for the high enthalpy of hydrolysis of the 3'-bond [5, 6]. In spite of the strained phosphate ring, cyclic AMP is stable in acidic or alkaline solutions, even at temperatures up to 100° C [7]. There is freedom of rotation around the glycosidic bond, as crystallography studies indicate the existence of two conformations around this bond [8], one of which assumes a more compact structure than the other (fig. 1). Cyclic AMP is formed from ATP, catalyzed by adenyl cyclase (reaction [I]), and hydrolyzed to 5'-AMP catalyzed by a specific phosphodiesterase (reaction [2]) [I]. Isotope experiments showed that the two reactions proceeded so strongly to the right that they could be considered essentially irreversible [6]. * The substance of this paper was presented at a Gordon Research Conference on "Cyclic AMP" held at Plymouth, New Hampshire, August 24-28, 1970. t Laboratory of Biochemistry, St. Jude Children's Research Hospital and Department of Biochemistry, University of Tennessee Medical Units, Memphis, Tennessee 38101. This work was supported by grants NS-08059 and CA-08480 from the U.S. Public Health Service, by ALSAC, and by a grant-in-aid from Eli Lilly & Company. The author is the recipient of a Research Career Development Award (1K4-NS-42576). Perspectives in Biology and Medicine · Winter 1972 | 221 Fig. 1.—The conformations of cyclic AMP are depicted with the Carey-Pauling atomic models in A and diagramatically in B. The configuration on the right assumes a more compact structure. For molecular dimensions of the two conformations the reader is referred to the original work of Waterpaugh et al. [8]. . ___ Adenyl Cyclase _ _ ATP ------------y Cyclic AMP + PPi „ Phosphodiesterase Cyclic AMP --------------y S'-AMP (D (2) Another point of interest is the low concentration of cyclic AMP in most tissues. At steady state, the tissue level is 10_ß m or lower, and is two to three orders of magnitude lower than other adenine nucleotides such as ATP (10-a m), ADP (I0~4 m), and 5'-AMP (10~4 m). The cyclic nucleotide appears to turn over at a rapid rate; for example, cyclic AMP levels in fat cells increased some twentyfold in the presence of epinephrine within minutes after the addition of theophylline , a known inhibitor of phosphodiesterase [9]. 222 I Wai Yiu Cheung · Adenosine 3', S'-Monophosphate According to the "second-messenger" concept [10], a hormone (the extracellular first messenger) interacts with a receptor site, thought to be an integral part of adenyl cyclase, and causes an increase of cyclic AMP (the intracellular second messenger) (fig. 2). The increase of cyclic AMP will produce different effects depending on the type of cell in which it occurs, and the hydrolysis of cyclic AMP to 5'-AMP by phosphodiesterase in turn terminates its physiological action. Functionally, adenyl cyclase serves as a transducer of hormonal signals , and phosphodiesterase, as a terminator of these signals. A simple mechanism consistent with these features and common to all the different processes affected by cyclic AMP would be that the nucleotide exerts its effects in an allosteric manner. This postulate implies that cyclic AMP, in interacting with a protein or proteins, does not initiate a new covalent bond and thus can be recovered in an unaltered form. In interacting with a protein, the nucloetide may be bound to the protein, provided that the nucleotide-protein complex is reasonably stable...