5 -Adenosine monophosphate hydrolysis

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes that catalyze the hydrolysis of 3, 5 -cyclic guanosine monophosphate (cGMP) or 3, 5 -cyclic adenosine monophosphate (cAMP) to 5 -guanosine monophosphate (GMP) or 5 -adenosine monophosphate (AMP), respectively. 

The effect of receptor stimulation is thus to catalyze a reaction cycle. This leads to considerable amplification of the initial signal. For example, in the process of visual excitation, the photoisomerization of one rhodopsin molecule leads to the activation of approximately 500 to 1000 transdudn (Gt) molecules, each of which in turn catalyzes the hydrolysis of many hundreds of cyclic guanosine monophosphate (cGMP) molecules by phosphodiesterase. Amplification in the adenylate cyclase cascade is less but still substantial each ligand-bound P-adrenoceptor activates approximately 10 to 20 Gs molecules, each of which in turn catalyzes the production of hundreds of cyclic adenosine monophosphate (cAMP) molecules by adenylate cyclase. 

A similar reaction mechanism was proposed by Chin et al. [32] for the hydrolysis of the biological phosphate monoester adenosine monophosphate (AMP) by the complex [(trpn) Co (OH2)]2+ [trpn = tris(ami-nopropyl)amine]. Rapid cleavage is observed only in the presence of 2 equiv metal complex. It is evident from 31P NMR spectra that on coordination of 1 equiv (trpn)Co to AMP a stable four-membered chelate complex 4 is formed. The second (trpn)Co molecule may bind to another oxygen atom of the substrate (formation of 5) and provide a Co-OH nucleophile which replaces the alkoxy group. The half-life of AMP in 5 is about 1 h at pD 5 and 25 °C. 

To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed Mi receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the Mi and M2 receptors occur in the brain. Recent studies have shown that Mi and M3 are located posts)maptically in the brain whereas the M2 and M4 receptors occur pres)maptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the Mi, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8). 

The nucleotide cyclic AMP (3, 5 -cyclic adenosine monophosphate, cAMP) is a cyclic phosphate ester of particular biochemical significance. It is formed from the triester ATP by the action of the enzyme adenylate cyclase, via nucleophilic attack of the ribose 3 -hydroxyl onto the nearest P=0 group, displacing diphosphate as leaving group. It is subsequently inactivated by hydrolysis to 5 -AMP through the action of a phosphodiesterase enzyme. 

There are two anhydride linkages in ATP, but nucleophilic attack in the enzyme-controlled reaction usually occurs on the terminal P=0 (hydrolysis of ATP to ADP), and only occasionally do we encounter attack on the central P=0 (hydrolysis of ATP to adenosine monophosphate, AMP). Both reactions yield the same amount of energy, AG—34 kJmoD This is not surprising, since in each case the same type of bond is being hydrolysed. The further hydrolysis of AMP to adenosine breaks an ester linkage and would liberate only a fraction of the energy, AG — 9 kJmol and this reaction is not biochemically important. 

FIGURE 8-6 Some adenosine monophosphates Adenosine 2 -monophosphate, 3 -monophosphate, and 2, 3 -cyclic monophosphate are formed by enzymatic and alkaline hydrolysis of RNA. 

The substance that is the immediate source of energy for many biological reactions is adenosine triphosphate (ATP). Although this is a rather large and complex molecule, the business end for the purpose of this discussion is the triphosphate group. Hydrolysis of this group can occur to give adenosine diphosphate (ADP), adenosine monophosphate (AMP), or adenosine itself ... 

SM2/AM1 and SM3/PM3 models were used to study the hydrolysis of pyrophosphate, which is coupled to virtually all biosynthetic reactions. However, the authors concluded that extreme care must be taken when applying semiempirical methods to compounds containing second-row atoms, since they may produce anomalously high atomic charges [98]. On the other hand, a study on syn and anti conformations of solvated cyclic 3 ,5 -adenosine monophosphate indicated that SM3/PM3 and SM2/AM1 models are inexpensive yet accurate approaches... 

Even more pronounced general acid catalysis by nucleoside monophosphates in the hydrolysis of diol epoxides 80 and 81 is observed.90 In Fig. 3 are plots of obsd versus total concentrations of guanosine (G), ribose S -phosphate, 5Ccytosine monophosphate (5 -CMP), 5 -adenosine monophosphate (5 -AMP) and 5Cguanosine... 

Nucleotide delivery systems based upon pH-driven selective chemical hydrolysis have been extended to 2, 3 -dideoxy-adenosine monophosphate (ddAMP) protected as the lipophilic cyclosaligenyl diester. The syntheses, lipophilic... 

Adrenoceptors are proteins embedded in the cell membrane that are coupled through a G-protein to effector mechanisms that translate conformational changes caused by activation of the receptor into a biochemical event within the cell. All of the )3-adrenoceptors are coupled through specific G-proteins (Gg) to the activation of adenylyl cyclase (45). When the receptor is stimulated by an agonist, adenylyl cyclase is activated to catalyze conversion of ATP to cyclic-adenosine monophosphate (cAMP), which diffuses through the cell for at least short distances to modulate biochemical events remote from the synaptic cleft. Modu-lationof biochemical events by cAMP includes a phosphorylation cascade of other proteins. cAMP is rapidly deactivated by hydrolysis of the phosphodiester bond by the enzyme phosphodiesterase. The a,-receptor may use more than one effector system, depending on the location of the receptor however, to date the best understood effector system of the a,-receptor appears to be similar to that of the )3-re-... 

The first two questions are relatively simple to answer. Adenosine, it will be remembered, is the nucleotide formed from adenine and ribose, and it can be phosphorylated to yield first adenosine monophosphate (AMP), then adenosine diphosphate (ADP) and finally ATP (see page 41). If we follow the course of its hydrolysis back to adenosine we find the following series of reactions ... 

ATP may be hydrolyzed to form ADP and P, (orthophosphate) or AMP (adenosine monophosphate) and PP, (pyrophosphate). Pyrophosphate may be subsequently hydrolyzed to orthophosphate, releasing additional free energy. The hydrolysis of ATP to form AMP and pyrophosphate is often used to drive reactions with high positive AG° values or to ensure that a reaction goes to completion. 

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