Phosphorylation, adenosine

Pyrazomycin. Pyrazomycin (11), 3-(l-p-D-ribofuranosyl)-4-hydroxypyrazole 5-carboxamide, is isolated from S. Candidas (1—4,9,10). The incorporation of [2-13C]acetate and [1- and U-14C]glutamate into the four contiguous carbons of pyrazomycin has been reported (11,12). Pyrazomycin 5 -phosphate inhibits orotidylic acid decarboxylase. Pyrazomycin inhibits adenosine phosphorylation and decreases the incorporation of deoxyuridine into DNA of Novikoff hepatoma cells in culture. It also inhibits the growth of tumor cells and the cytopathic effects of vaccinia, herpes simplex, vesicular stomatitis, Newcasde disease, measles, Sindbis, polio, hepatitis A, and coxsackie viruses (13,14). The inhibitory action of (11) on viral multiplication is reversed by uridine. 

Just as in the case of N, the source of the sulphur of higher plants is an oxidized form, namely sulphate. And just like nitrate, sulphate must first be reduced. Ultimately, sulphur is present in the doubly negative form as S. The first step in the assimilation of S is the fixation of sulphate. This is brought about by sulphate reacting with ATP to liberate pyrophosphate. An adenosine-phosphate-sulphate compound is formed and to the ribose of this compound another phosphate residue from another ATP molecule is attached. The product thus obtained is 3 -phosphoryl-5 -adenosine-phosphoryl-sulphate or simply active sulphate (Fig. 114). In this way sulphur is fixed and activated. It is this bound form of active sulphate which is subjected to reduction to the level of S. It is likely that 2 electron transitions are also implicated here. The mechanism is still unknown. 

In another contribution the Fischer s team showed that dAMP and dGMP molecules decorated with an additional 3 -0-phosphate (26) and adenosine phosphorylated at both 2 and 3 -positions (27), as well as their phosphorothioate analogues, exert a dual antioxidant activity, acting as both metal-ion chelators and radical scavengers. ... 

Phosphorus. Eighty-five percent of the phosphoms, the second most abundant element in the human body, is located in bones and teeth (24,35). Whereas there is constant exchange of calcium and phosphoms between bones and blood, there is very Httle turnover in teeth (25). The Ca P ratio in bones is constant at about 2 1. Every tissue and cell contains phosphoms, generally as a salt or ester of mono-, di-, or tribasic phosphoric acid, as phosphoHpids, or as phosphorylated sugars (24). Phosphoms is involved in a large number and wide variety of metaboHc functions. Examples are carbohydrate metaboHsm (36,37), adenosine triphosphate (ATP) from fatty acid metaboHsm (38), and oxidative phosphorylation (36,39). Common food sources rich in phosphoms are Hsted in Table 5 (see also Phosphorus compounds). 

The modes of action for niclosamide are interference with respiration and blockade of glucose uptake. It uncouples oxidative phosphorylation in both mammalian and taenioid mitochondria (22,23), inhibiting the anaerobic incorporation of inorganic phosphate into adenosine triphosphate (ATP). Tapeworms are very sensitive to niclosamide because they depend on the anaerobic metaboHsm of carbohydrates as their major source of energy. Niclosamide has selective toxicity for the parasites as compared with the host because Httle niclosamide is absorbed from the gastrointestinal tract. Adverse effects are uncommon, except for occasional gastrointestinal upset. 

Ara-A is phosphorylated in mammalian cells to ara-AMP by adenosine kinase and deoxycytidine kinase. Further phosphorylation to the di- and triphosphates, ara-ADP and ara-ATP, also occurs. In HSV-1 infected cells, ara-A also is converted to ara-ATP. Levels of ara-ATP correlate directly with HSV rephcation. It has recently been suggested that ara-A also may exhibit an antiviral effect against adenovims by inhibiting polyadenylation of viral messenger RNA (mRNA), which may then inhibit the proper transport of the viral mRNA from the cell nucleus. 

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... 

A good example of an affinity label for creatine kinase has been presented (35). This enzyme catalyzes the reversible transfer of a phosphoryl group from adenosine triphosphate [56-65-5] (17) to creatine [57-00-1] (18), leading to adenosine diphosphate [7584-99-8] (19) and phosphocreatine [67-07-2]... 

The first pharmacological agent shown to activate AMPK was 5-aminoimidazole-4-carboxamide (AICA) riboside, also known as acadesine. This adenosine analogue is taken up into cells by adenosine transporters and phosphoiylated by adenosine kinase to the mono-phosphorylated form, AICA ribotide or ZMP. ZMP accumulates inside cells to higher concentrations than the concentration of AICA riboside present in the medium, and it mimics both effects of AMP on AMPK system (allosteric activation and inhibition of... 

The major relaxing transmitters are those that elevate the cAMP or cGMP concentration (Fig. 3). Adenosine stimulates the activity of cAMP kinase. The next step is not clear, but evidence has been accumulated that cAMP kinase decreases the calcium sensitivity of the contractile machinery. In vitro, cAMP kinase phosphorylated MLCK and decreased thereby the affinity of MLCK for calcium-calmodulin. However, this regulation does not occur in intact smooth muscle. Possible other substrate candidates for cAMP kinase are the heat stable protein HSP 20, (A heat stable protein of 20 kDa that is phosphorylated by cGMP kinase. It has been postulated that phospho-HSP 20 interferes with the interaction between actin and myosin allowing thereby smooth muscle relaxation without dephosphorylation of the rMLC.) Rho A and MLCP that are phosphorylated also by cGMP kinase I (Fig. 3). 

From this observation of the inhibition by adenosine, and other observations, Newell and Tucker suspected the existence of a common synthetic pathway for adenosine and thiamine, and proved (with the help of a collection of mutants) that the bifurcation occurred after the 5-amino- l-(P-D-ribofura-nosyl)imidazole 5 -phosphate (46) step (Scheme 23). Finally, they found that 5-amino-l-(0-D-ribofuranosyl)imidazole (47), labeled with l4C in the imidazole ring, was incorporated into pyramine without significant loss of molar radioactivity by a mutant that is able to use this nucleoside (presumably after phosphorylation).53,54... 

If MLCK activates contraction by increasing myosin phosphorylation, then an increase in the activity of myosin light chain phosphatase, MLCP, by decreasing the fraction of myosin which is phosphorylated, should lead to relaxation from the active (contractile) state. Cyclic adenosine monophosphate (AMP) is a strong inhibitor of smooth muscle contraction and it has been suggested that activation of MLCP could result from its phosphorylation via cAMP activated protein kinase (see Figure 5). 

Adenosine kinase catalyzes phosphorylation of adenosine and deoxyadenosine to AMP and dAMP, and de-oxycytidine kinase phosphorylates deoxycytidine and 2 -deoxyguanosine to dCMP and dGMP. 

Figure 13.1 Chemical structures of, and relationship between, adenosine and adenosine 5 -triphosphate (ATP). Adenosine contains an adenine ring and ribose component. Phosphorylation of the latter s termial (C5) hydroxy with three phosphate groups gives ATP...

When AMP is heated under reflux in DMF, the 2, 3 -cyclic phosphate is formed, and cyclic phosphates can also be obtained from nucleosides and ortho-, pyro-, or poly-phosphoric acids under the same conditions. Promotion of phosphorylation by DMF is well known and the reaction with AMP is probably intermolecular as no 3, 5 -cyclic AMP can be detected. Minor products in the latter reaction are the 2, 3 -cyclic 5 -diphosphate and the 2 (30,5 -diphosphate. The synthesis of adenosine 2 (3 )-phosphate 5 -pyrophosphate has been achieved by the phosphoromorpholidate method used in a synthesis of Co A. ... 

Adenosine 5 -hypophosphate (23), an analogue of ADP, can undergo phosphorylation by PEP and pyruvate kinase to yield (24). Adenylate kinase which catalyses the scission of the bond between the a and j8 phosphorus atoms in ADP is, not surprisingly, inhibited competitively by (23). 

A remarkable feature of the bioenergetic oxidation reactions of nutrients in cells is the fact that they are always coupled to another reaction, that of synthesis of the energy-rich chemical substance adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate (oxidative phosphorylation Engelgardt and Ljubimova, 1939) ... 

DNA and RNA are formed of nucleotides. Each nucleotide or nucleoside is composed of a purine or pyrimidine base linked to the 1-position of a ribose sugar in the case of RNA and a 2 -deoxyribose sugar in the case of DNA.155 The 5 position is phosphorylated in the case of a nucleotide, while the nucleoside is not phosphorylated therefore, nucleotides are nucleoside phosphates. Phosphorylation can include one, two, or three phosphate groups. The most familiar example of a phosphorylated nucleotide is phosphorylated adenosine, which occurs as the mono-, di-, and triphosphate (AMP, ADP, and ATP, respectively) and is a principal means of energy storage in biological systems. 

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