Adenosine 3,5-Phosphate Phosphodiesterases

Adenosine 3, 5 -Phosphate Phosphodiesterases.—Since it interacted with immobilized concanavalin A, an adenosine 3, 5 -phosphate phosphodiesterase from Dictyostelium discoideum appears to be a glycoprotein.  

Dextransucrases.—A dextransucrase from the cell-free supernatant fluid of cultures of Leuconostoc mesenteroides has been separated into two active forms, 

Hatanaka, F. Egami, I. Ishizuka, and Y. Nagai, Biochim. Biophys. Acta, 1976, 438, 176. 

Okamura, T. Yamaoa, Y. Muraoka, and T. Harada, Agric. and Biol. Chem. Japan), 1976, 40, 2071. 

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P-D-2-Acetamido-2-deoxy-hexosidase Acetylcholinesterase Adenosine 3, 5 -phosphate phosphodiesterase Aldose-ketose isomerases (general)... 

Condensation of 2-amino-3-bromo-l,6-naphthyridines 81 with potassium O-ethyl xanthate in A-methylpyrrolidone afforded thiazolo[4,5-6][l,6]naphthyridine-2(3//)-thiones 303 whose subsequent methylation and hydrolysis in the presence of sodium methoxide afforded thiazolonaphthyridones 304 inhibiting adenosine-3, 5 -cyclo-phosphate phosphodiesterase (cAMP PDE III) (1995JMC2546). 

In 1949, Cohn applied ion-exchange chromatography to the separation of nucleic acid derivatives and demonstrated elegant separations of nucleotides on anion-exchange resins such as Dowex-1 (which has quaternary ammonium charged groups on a polystyrene matrix). It was shown at that time that both RNA and DNA could be hydrolyzed by phosphodiesterases to yield nucleoside 5 -phosphates and it was therefore evident that polynucleotides could be regarded as assemblies of nucleoside 5 -phosphates. At this point, the adenosine phosphates were the only free nucleotides known to occur in tissues, apart from the coenzymes. Because the free adenosine phosphates were 5 -esters, a precursor relationship between these compounds and the pol mucleotides seemed likely. 

W. H. Moos, C. C. Humblet, 1. Sircar, C. Rithner, R. E. Weishaar, J. A. Bristol, and A. T. McPhail, /. Med. Chem., 30,1963 (1987). Cardiotonic Agents. 8. Selective Inhibitors of Adenosine 3, 5 -Cyclic Phosphate Phosphodiesterase III. Elaboration of a Five-Point Model for Positive inotropic Activity. 

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. 

FAD is cleaved by an FAD-adenosine monophosphate (AMP) lyase in liver to yield AMP and riboflavin 4, 5 -cyclic phosphate it is not known whether this has any coenzyme or cell signaling function, but it is a substrate for phosphodiesterase and has also been identified in small amounts in yeast (Fraiz et al., 1998 Cabezas et al., 2001). 

Gulland and Jackson performed some experiments with 5-nucleotidase, a highly specific enzyme which dephosphorylates 5-phospho-adenosine and -inosine but not" 5-phospho-guanosine and -uridine it is apparently not yet known whether the enzyme dephosphorylates 5-phos-pho-cytidine. They found that a mixture of phosphodiesterase with 5-nucleotidase liberates 35% of the total phosphorus as inorganic phosphate, and therefore decided that two or more of the phosphoryl groups may be attached at position (5) of the ribose units. The 35% dephosphorylation, intermediate between 25 and 50%, was explained as the result of simultaneous, competitive diesterase action at A and B, on two or more phosphoryl groups ... 

The promotion of the synthesis of lipids (lipogenesis) and the inhibition of the release of free fatty acids (lipolysis) by insulin also requires a complex network of signalling pathways, partially coupled to those for the Glut4 activation. In adipocytes, insulin inhibits lipolysis primarily through inhibition of a hormone-sensitive lipase via reduction of the amount of cyclic adenosine monophosphate (cAMP) present in the cells. In this specific action, a phosphodiesterase is involved, ] a level where again the phosphate antagonist vanadate can interfere. 

Butcher, R.W., and Sutherland, E.W. (1962) Adenosine 3, 5 -phosphate in biological materials. I. Purification and properties of cyclic 3, 5 -nucleotide phosphodiesterase... 

A uridine phosphate (5), obtained by treatment of uridine 5 -(a-D-glucopyranosyl pyrophosphate) with ammonia, imdergoes hydrazinolysis to D-ribose 5-phosphate (2) and 3-pyrazolone, which establishes the structure of (S) as uridine 5 -phosphate. - (Hydrazinolysis of uridine to pyrazolone, with the liberation of the sugar moiety, had been described, and has served as a useful tool in the determination of the position of attachment of the sugar moiety to the aglycon. ) The 5 -phosphates of adenosine, guanosine, cytidine, and uridine were obtained by enzymic hydrolysis of ribonucleic acid with phosphodiesterases from snake venom and from other sources (such as Streptomyces aureu ). 

Alkyl halides are even less reactive than acyl halides, as indicated by the compilation of reaction rates of thiolate anions with various types of alkyl halides (282). Nevertheless, potentially useful affinity labels have been synthesized with alkyl halide substituents and have been shown to specifically inactivate several enzymes, albeit slowly the low reactivity of the alkyl halides may minimize nonspecific reaction. Adenosine 5 -(2-bromoethyl)phosphate has been characterized and reported to inactivate NAD -dependent isocitrate dehydrogenase (283). The 2 - and 3 -(2-bromoethyl)-AMP labels have also been synthesized, and model reactions of the bromoethyl-AMPs with cysteine, lysine, histidine, and tyrosine have been studied (284). More recently, esters of adenosine 5 -monophosphate have been prepared with ethyl, propyl, or hexyl moieties and bromo or chloro substituents at the w position (285). Yeast alcohol dehydrogenase exhibited enhanced inactivation by the hexyl derivative, but inactivation rates of other dehydrogenases were unremarkable. Two iodopropyl derivatives of cAMP have been described, namely, 1, A -(3-iodopropyleno)adenosine 3, 5 -cyclic monophosphate and 3 -0-(2-iodo-3-hydroxypropyl)adenosine 3, 5 -cyclic monophosphate the latter inactivates cAMP phosphodiesterase from human platelets, with a pseudo-first-order rate constant of 0.147 hr" (286). 

The 3, 5 -cyclic monophosphate of adenosine (cAMP) (2.148) is an important secondary messenger for intercellular communication in biochemistry. When the cell is stimulated by the first messenger, compound 2.148 is formed from adenosine triphosphate (ATP) (Scheme 2.25). This reaction is catalysed by an adenosine cyclase enzyme. The cAMP then goes on to activate other intracellular enzymes, so producing a cell response. The response is terminated by the hydrolysis of cAMP by phosphodiesterase (a phosphate-ester-hydrolysis enzyme). The action of adenylate cyclase has been mimicked successfully with a p-cyclodextrin complex of Pr(iii) and other lanthanide(iii) metals, under physiological conditions. The... 

Bull seminal plasma also contains 5-nucleotidase activity. The enzyme has been purified from this source and found to split adenosine-5 -phosphate, uridine-5 -phosphate, cytidine-5 -phosphate, guanosine-5 -phosphate, and nicotinamide-ribose-5 -phosphate. Of several dozen other esters, only the desoxyribonucleotides have been found active as substrates. Snake venom contains a highly specific 5-nucleotidase which can be separated from phosphodiesterase by means of cellulose column chromatography. ... 

It seems likely that the metabolic effects of several hormones are mediated by adenosine 3, 5 -phosphate (cyclic AMP). The biochemical effects of this nucleotide have been discussed. 3-92 Cyclic AMP is synthesized from ATP by a reaction catalyzed by adenyl cyclase and it is rapidly inactivated by a cyclic 3, 5 -nucleotide phosphodiesterase which converts it to 5 -AMP.91 Cyclic AMP levels are Influenced by numerous hormones, (catecholamines, glucagon, ACTH, Insulin, and others).91 Most of these stimulate adenyl cyclase and Increase cyclic AMP levels, however, insulin... 

The first biochemical effect described was the inhibition of phosphodiesterase, the enzyme that catalyzes the breakdown of cyclic adenosine 3, 5 -phosphate (cAMP). Caffeine was shown to increase cAMP concentrations in various tissues. This inhibition occurs at large concentrations (millimolar range) and is of limited importance with regard to the physiological effects of caffeine at levels at which it is normally consumed. 

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