Phosphorylation, adenosine mechanism

Adenosine triphosphate, ATP4-, is the body s energy currency and a Y-L sink. It activates compounds by phosphorylation. The mechanism of the enzyme glycerol kinase (Fig. 8.1) is postulated to go by a pentacovalent phosphorus intermediate. A base in the active site makes the oxygen lone pair more nucleophilic by deprotonating it as it attacks... 

One mechanism that has been proposed to explain the hepatotoxicity of 1,1,2-trichloroethane is the generation of free radical intermediates from reactive metabolites of 1,1,2-trichloroethane (acyl chlorides). Free radicals may stimulate lipid peroxidation which, in turn, may induce liver injury (Albano et al. 1985). However, Klaassen and Plaa (1969) found no evidence of lipid peroxidation in rats given near-lethal doses of 1,1,2-trichloroethane by intraperitoneal injection. Takano and Miyazaki (1982) determined that 1,1,2-trichloroethane inhibits intracellular respiration by blocking the electron transport system from reduced nicotinamide adenine dinucleotide (NADH) to coenzyme Q (CoQ), which would deprive the cell of energy required to phosphorylate adenosine diphosphate (ADP) and thereby lead to depletion of energy stores. 

In the presence of calcium, the primary contractile protein, myosin, is phosphorylated by the myosin light-chain kinase initiating the subsequent actin-activation of the myosin adenosine triphosphate activity and resulting in muscle contraction. Removal of calcium inactivates the kinase and allows the myosin light chain to dephosphorylate myosin which results in muscle relaxation. Therefore the general biochemical mechanism for the muscle contractile process is dependent on the avaUabUity of a sufficient intraceUular calcium concentration. 

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... 

Metabotropic receptors, in contrast, create their effects by activating an intracellular G protein. The metabotropic receptors are monomers with seven transmembrane domains. The activated G protein, in turn, may activate an ion channel from an intracellular site. Alternately, G proteins work by activation or inhibition of enzymes that produce intracellular messengers. For example, activation of adenylate cyclase increases production of cyclic adenosine monophosphate (cAMP). Other effector mechanisms include activation of phospholipases, diacylglycerol, creation of inositol phosphates, and production of arachidonic acid products. Ultimately, these cascades can result in protein phosphorylation. 

Sulfation in most aspects is very similar to phosphorylation, except that sulfation is not involved in intracellular signal transduction, but in other forms of signaling. The mechanism of sulfation is similar to that of phosphorylation as a general base from the enzyme active site that deprotonates the hydroxyl groups of tyrosine residues. The nucleophilic oxygen then attacks the /3-position, in contrast to the 7-position in phosphorylation, and releases adenosine 3, 5 -diphosphate. 

Palmer, T. M., Benovic, J. L., and Stiles, G. L. (1995) Agonist-dependent phosphorylation and desensitization of the rat A3 adenosine receptor. Evidence for a G-protein-conpled receptor kinase- mediated mechanism. J. Biol. Chem. 270, 29607-29613. 

Figure 22.17 Summary of mechanisms to maintain the ATP/ADP concentration ratio in hypoxic myocardium. A decrease in the ATP/ADP concentration ratio increases the concentrations of AMP and phosphate, which stimulate conversion of glycogen/ glucose to lactic acid and hence ATP generation from glycolysis. The changes also increase the activity of AMP deaminase, which increases the formation and hence the concentration of adenosine. The latter has two major effects, (i) It relaxes smooth muscle in the arterioles, which results in vasodilation that provides more oxygen for aerobic ATP generation (oxidative phosphorylation). (ii) It results in decreased work by the heart (i.e. decrease in contractile activity), (mechanisms given in the text) which decreases ATP utilisation.

There is evidence (but not conclusive evidence) that the mechanisms involves direct phosphoryl transfer to water rather than the formation of a phosphoenzyme intermediate.293 This utilizes the fact that ATP also serves as a substrate to inorganic pyrophosphatase. Hydrolysis of the ATP analogue adenosine 5 -0-(3-thiotriphosphate) chirally labelled with I70 and I80 at the y-phosphate proceeds with inversion of configuration to give the chiral [170,180]-thiophosphate (Figure 13).293... 

RNase A can use one-dimensional diffusion along a poly(dA) tract to accelerate the location of a uridine substrate. Use of this mechanism depends on the concentration of NaCl, as expected if the enzyme were binding to the nucleic acid by nonspecific interactions with phosphoryl groups. Binding of the enzymic active site to adenosine residues is 20-fold weaker than to uridine residues, which could enhance the ability of the enzyme to slide along the poly(dA) tract. 

Several reviews of the clinical pharmacology, actions, therapeutic uses, and adverse reactions and interactions of adenosine and ATP have appeared (1-4). After intravenous administration adenosine enters cells, disappearing from the blood with a half-life of less than 10 seconds intracellularly it is phosphorylated to cyclic AMP. Its mechanism of action as an antidysrhythmic drug is not known, but it may act by an effect at adenosine receptors on the cell membrane. Its electrophysiological effects are to prolong AV nodal conduction time by prolonging the AH interval, without an effect on the HV interval. The pharmacological and adverse effects of adenosine triphosphate are similar to those of adenosine. 

Chlorophenols block adenosine triphosphate (ATP) production, without blocking the electron transport chain. They inhibit oxidative phosphorylation, which increases basal metabolic rate and increases body temperature. As body temperature rises, heat-dissipating mechanisms are overcome and metabolism is accelerated. Adenosine diphosphate (ADP) and other substrates accumulate, and stimulate the electron transport chain further. This process demands more oxygen in a futile effort to produce ATP. Oxygen demand quickly surpasses oxygen supply and energy reserves of the body become depleted. 

Thallium s mechanism of toxicity is related to its ability to interfere with potassium ion functions. Thallium interferes with energy production at essential steps in glycolysis, the Kreb s cycle, and oxidative phosphorylation. Other effects include inhibition of sodium-potassium-adenosine triphosphatase and binding to sulfhydryl groups. 

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-... 

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