Adenosine deaminase, action

Adenosine is formed from ATP via a phosphatase cascade that sequentially involves the diphosphate, ADP, and the monophosphate, AMP. The actions of adenosine are terminated by uptake and rephosphorylation via adenosine kinase to AMP or by cataboHsm via adenosine deaminase to inosine and hypoxanthine. 

The antiviral activity of (5)-DHPA in vivo was assessed in mice inoculated intranasaHy with vesicular stomatitis vims ( 5)-DHPA significantly increased survival from the infection. (5)-DHPA did not significantly reduce DNA, RNA, or protein synthesis and is not a substrate for adenosine deaminase of either bacterial or mammalian origin. However, (5)-DHPA strongly inhibits deamination of adenosine and ara-A by adenosine deaminase. Its mode of action may be inhibition of Vadenosyl-L-homocysteine hydrolase (61). Inhibition of SAH hydrolase results in the accumulation of SAH, which is a product inhibitor of Vadenosylmethionine-dependent methylation reactions. Such methylations are required for the maturation of vital mRNA, and hence inhibitors of SAH hydrolase may be expected to block vims repHcation by interference with viral mRNA methylation. 

Pentostatin (deoxycoformycin Fig. 4) is a purine isolated from cultures of Streptomyces antibioticus. Its mode of action involves inhibition of adenosine deaminase, which plays a key role in purine salvage pathways and DNA synthesis. As a consequence, deoxyadenosine triphosphate (dATP) is accumulated, which is highly toxic to lymphocytes. This is associated with augmented susceptibility to apoptosis, particularly in T cells. 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

Adenine is deaminated to inosine by the action of adenosine deaminase. 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Mechanism of Action A blood modifier and platelet aggregation inhibitor that inhibits the activity of adenosine deaminase and phosphodiesterase, enzymes causing accumulation of adenosine and cyclic adenosine monophosphate. Therapeutic Effect Inhibits platelet aggregation may cause coronary vasodilation. 

Actions Adenosine deaminase stimulator, genetically engineered autologous cell therapy, immunomodulator, retrovirus-based gene therapy... 

Purine nucleotides are degraded by a pathway in which they lose their phosphate through the action of 5 -nucleotidase (Fig. 22-45). Adenylate yields adenosine, which is deaminated to inosine by adenosine deaminase, and inosine is hydrolyzed to hypoxanthine (its purine base) and D-ribose. Hypoxanthine is oxidized successively to xanthine and then uric acid by xanthine oxidase, a flavoenzyme with an atom of molybdenum and four iron-sulfur centers in its prosthetic group. Molecular oxygen is the electron acceptor in this complex reaction. 

Fig. 4 Mechanisms involved in the extracellular inactivation of nucleotides (a, b and c) and adenosine (d) and their influence on purine concentration in the P2Y and PI receptor biophases, (a) NT-PDasel hydrolyses ATP and ADP very efficiently, thus preventing their action on P2Y receptors (b) NTPDase2 metabolizes ATP preferentially, allowing an accumulation of ADP and thus favouring activation of P2Yi, 12,13 receptors (c) NTPDase3 hydrolyses both ATP and ADP slowly, giving them time to activate both P2Y2,4 and P2Y 1,12,13 receptors. Formation of adenosine depends on the activity of ecto 5 -nucleotidase (CD73). Adenosine inactivation systems also influence adenosine concentration in the PI receptor biophase (d) the nucleoside transporters take up adenosine adenosine deaminase (ADA) regulates both the concentration of adenosine in the Ai receptor biophase and the functionality of Ai receptors.

As with almost all systemic fungicides, after foliar or soil application, absorption and translocation via the xylem follows. The mechanisms of action of pyrimidines are not very clear, however, information suggests that spore germination and mycelial growth are inhibited. In addition, studies with ethirimol suggest that it inhibits RNA synthesis as well as adenosine metabolism by blocking adenosine deaminase. 

The ///t-berizoadenosine is hy drolyzed to //tr-benzoinosine by the action of adenosine deaminase. For the synthesis of various compounds of this series sec refs 25-27. 

The nucleoside 8-azaadenosine (monohydrate) was found to have a conformation intermediate between syn and anti (with a torsion angle of 104°) around the glycosyl - nitrogen bond, apparently stabilized by an electrostatic attraction between N-8 and C-2. Adenosine deaminase, which can not deaminate any analogs with a syn conformation, has only a feeble action on this nucleoside. ... 

Methoxy-, 6-ethoxy-, and 6-methylthio-9-ribofuranosyl-8-azapurines turned out to be substrates for adenosine kinase, and the first two examples were bound by adenosine deaminase. Their cytotoxic action was attributed to affinity for the kinase. 6-Imino-9-phenyl-l,6-dihydro-8-azapurine was found to be an efficient inhibitor of adenosine deaminase and guanine deaminase. Xanthine oxidase was inhibited by both this compound and 9-aryl-8-azapurin-6-ones. ° ... 

A set of 4-amino-3-aryltriazoles, each one further substituted by a 5-amide, -ester, or -nitrile group, inhibited these enzymes adenosine deaminase, guanine deaminase, and xanthine oxidase. Structure-action relationships were discussed (79MI1 85FES73). 

Dipyridamole is a potent coronary vasodilator. Despite the fact that it causes a substantial increase in CBF, its value for the acute relief or prevention of angina pectoris has been seriously questioned. Considerable effort has been expended in the study of this drug. Deutllcke reports dipyridamole to inhibit adenosine deaminase which results in an accumulation of adenosine. Since adenosine is a potent vasodilator, there is an increase in CBF. Emmons found dipyridamole to inhibit platelet agglutination and proposed that dipyridamole prevents the uptake of adenosine by red blood cells, thereby delaying its deamination. Stafford feels that dipyridamole inhibition of adenosine deaminase is unlikely, as high concentrations are necessary to produce inhibition of deaminase from intestinal mucosa. Much lower concentrations of dipyridamole potentiate the action of adenosine on myocardial tissue. Stafford proposes that dipyridamole prevents the uptake of adenosine by myocardial tissue or red blood... 

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