Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the hydrated adenosine intermediate (6R)-6-amino-1, 6-dihydro-6-hydroxy-9-(beta-D-ribofuranosyl)purine (2) produced by adenosine deaminase (ADA, EC 3.5.4.4) as a starting point, the active site probe and inhibitor platform 5-(formylamino)imidazole riboside (FAIRs, 4) was designed by removal of the-C6(OH)(NH2)-molecular fragment of 2 generated by the early events of the enzyme-catalyzed hydrolysis. FAIRs was synthesized directly from the sodium salt of 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxylic acid (CAIR) along a reaction sequence involving a tandem N-formylation/decarboxylation that may have a mechanistic connection to the Escherichia coli purE-catalyzed constitutional isomerization of N5-CAIR to CAIR. The physical and spectral properties of FAIRs were elucidated, its X-ray crystal and NMR solution structures were determined, and its interaction with ADA was investigated. Crystalline FAIRs exists solely as the Z-formamide rotamer and exhibits many of the same intramolecular hydrogen bonding events known to contribute to the association of Ado to ADA. In water and various organic solvents, however, FAIRs exists as NMR-distinct, slowly interconverting Z and E rotamers. This truncated enzymatic tetrahedral intermediate analog was determined to be a competitive inhibitor of ADA with an apparent Ki binding constant of 40 microM, a value quite close to that (33 microM) of the natural substrate's K(m). The actual species selected for binding by ADA, though, is likely the minor hydroxyimino prototropic form of Z-FAIRs possessing a far lower true Ki value. As the structural features of FAIRs appear well-suited to support its use as a template for constructing active site probes of both ADA and AIR carboxylases, a variety of carbohydrate-protected versions of FAIRs suitable for facile aglycon elaborations were synthesized. The N3-alkylation, N3-borane complexation, and C4-iodination of some of these were investigated in order to assess physicochemical properties that may assist in the elucidation of mechanisms for the AIR carboxylases. The survey of these properties taken together with a reasonable mechanism for the model CAIRs-->FAIRs synthetic transformation is interpreted to support a mechanism for the purE-catalyzed N5-CAIR-->CAIR biosynthetic one that involves a carboxylative sp3-rehybridization of the imidazole C4 atom rather than one possessing a dipole-stabilized C4 sp2 carbanionic intermediate.
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PMID:Effect of a chemical modification on the hydrated adenosine intermediate produced by adenosine deaminase and a model reaction for a potential mechanism of action of 5-aminoimidazole ribonucleotide carboxylase. 934 8

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2', 3'-dideoxyadenosine (ddA) (2) and 2',3'-dideoxy-2', 3'-didehydroadenosine (d4A) (3) are reported. These potential pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled, chemically induced tandem reaction. All new compounds 9 and 10a-d were synthesized in good yields using our previously reported phosphorus(III) method starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixture phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than the parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditions releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Further hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, respectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furthermore, all triesters 9 and 10 were markedly more active than the corresponding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenosine monophosphate deaminase (AMPDA) showed that the triesters were not substrates for enzymatic deamination. The studies reported herein demonstrate conclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also under intracellular conditions fulfilling the adenosine deaminase bypass premise.
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PMID:cycloSal-Pronucleotides of 2',3'-dideoxyadenosine and 2', 3'-dideoxy-2',3'-didehydroadenosine: synthesis and antiviral evaluation of a highly efficient nucleotide delivery system. 1022 29

Polymer conjugation is of increasing interest in pharmaceutical chemistry for delivering drugs of simple structure or complex compounds such peptides, enzymes and oligonucleotides. For long time drugs, mainly with antitumoral activity, have been coupled to natural or synthetic polymers with the purpose of increasing their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. However only recently complex constructs were devised that exploit the 'enhanced permeability and retention' (EPR) effect for an efficient tumor targeting, the high molecular weight for adsorption or receptor mediated endocytosis and finally a lysosomotropic targeting, taking advantage of acid labile bonds or cathepsin susceptible polypeptide spacers between polymer and drug. New original, very active conjugates of this type, as those based on poly(hydroxyacrylate) polymers, are already in advanced state of development. Labile oligonucleotides, including antisense drugs, were also successfully coupled to polymers in view of an increased cell penetration and stabilization towards nucleases. However, the most active research activity resides in the field of polypeptides and proteins delivery, mainly for the two following reasons: first of all because a great number of therapeutically interesting compounds are now being produced by genetic engineering in large quantity and, secondly, because these products are difficult to administer to patients for several inherent drawbacks. Proteins are in fact easily digested by many endo- and exo-peptidases present in blood or in other body districts; most of them are immunogenic to some extent and, finally, they are rapidly excreted by kidney ultrafiltration. Covalent polymer conjugation at protein surface was demonstrated to reduce or eliminate these problems, since the bound polymer behaves like a shield hindering the approach of proteolytic enzymes, antibodies, or antigen processing cell. Furthermore, the increase of the molecular weight of the conjugate allows to overcome the kidney elimination threshold. Many successful results were already obtained in peptides and proteins, conjugated mainly to water soluble or amphiphilic polymers like poly(ethylene glycol) (PEG), dextrans, or styrenemaleic acid anhydride. Among the most successful are the conjugates of asparaginase, interleukin-2 or -6 and neocarcinostatin, to remind some antitumor agents, adenosine deaminase employed in a genetic desease treatment, superoxide dismutase as scavenger of toxic radicals, hemoglobin as oxygen carrier and urokinase and streptokinase as proteins with antithrombotic activity. In pharmaceutical chemistry the conjugation with polymers is also of great importance for synthetic applications since many enzymes without loss of catalytic activity become soluble in organic solvents where many drug precursors are. The various and often difficult chemical problems encountered in conjugation of so many different products prompted the development of many synthetic procedures, all characterized by high specificity and mild condition of reaction, now known as 'bioconjugation chemistry'. Bioconjugation developed also the design of new tailor-made polymers with the wanted molecular weight, shape, structure and with the functional groups needed for coupling at the wanted positions in the chain.
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PMID:Bioconjugation in pharmaceutical chemistry. 1051 Aug 47

The administration of anthocyanin dyes from Aronia melanocarpa in the rats before the intraperitoneal injections of PAF and ceruleine have a beneficial effect on the development of the acute experimental pancreatitis. It was revealed the reduction of pancreas swelling and decreasing of lipid peroxidation and adenosine deaminase activity. The examination was carried out on 149, weighing 200-250 g, female and male Wistar rats. They lived in the animal quarters with a stable temperature and humidity being fed with standard fodder (Murigan) and water ad libitum.
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PMID:[The influence of Aronia melanocapra in experimental pancreatitis]. 1096 16

(-)-beta-D-2,6-Diaminopurine dioxolane (DAPD), is a nucleoside reverse transcriptase (RT) inhibitor with activity against human immunodeficiency virus type 1 (HIV-1). DAPD, which was designed as a water-soluble prodrug, is deaminated by adenosine deaminase to give (-)-beta-D-dioxolane guanine (DXG). By using calf adenosine deaminase a K(m) value of 15 +/- 0.7 microM was determined for DAPD, which was similar to the K(m) value for adenosine. However, the k(cat) for DAPD was 540-fold slower than the k(cat) for adenosine. In CEM cells and peripheral blood mononuclear cells exposed to DAPD or DXG, only the 5'-triphosphate of DXG (DXG-TP) was detected. DXG-TP is a potent alternative substrate inhibitor of HIV-1 RT. Rapid transient kinetic studies show the efficiency of incorporation for DXG-TP to be lower than that measured for the natural substrate, 2'-deoxyguanosine 5'-triphosphate. DXG-TP is a weak inhibitor of human DNA polymerases alpha and beta. Against the large subunit of human DNA polymerase gamma a K(i) value of 4.3 +/- 0.4 microM was determined for DXG-TP. DXG showed little or no cytotoxicity and no mitochondrial toxicity at the concentrations tested.
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PMID:Mechanism of action of 1-beta-D-2,6-diaminopurine dioxolane, a prodrug of the human immunodeficiency virus type 1 inhibitor 1-beta-D-dioxolane guanosine. 1112 Sep 59

Renal sodium handling is important for regulating BP, and renal dopamine and adenosine play an important role in renal sodium handling, however the interaction of these hormones in the kidney was not clarified. In in vivo experiments, adenosine significantly increased water and sodium excretion by 50% compared with vehicle when infused into the left renal artery, accompanied by an increase in urinary dopamine excretion in the left kidney. Neither water-sodium excretion nor dopamine excretion changed in the vehicle-infused kidney. Aromatic L-amino acid decarboxylase activity in the left kidney was significantly higher than that in the noninfused right kidney. The increase in water-sodium excretion induced by adenosine was significantly inhibited by SCH23390, a selective D1 receptor antagonist. In in vitro experiments, porcine renal proximal tubular cells were incubated with 250 microM L-dopa and N(6)-cyclohexyladenosine, an adenosine type 1 receptor agonist, after treatment with adenosine deaminase. N(6)-cyclohexyladenosine significantly increased dopamine formation at a concentration of 10(-9) to 10(-7) M, and this was completely inhibited by 1,3-dipropyl-8-cyclopentylxanthin, an adenosine A1 antagonist. These results show that renal dopamine synthesis is stimulated by adenosine through the activation of aromatic L-amino acid decarboxylase and suggest that adenosine leads to an increase in renal dopamine and natriuresis.
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PMID:Adenosine activates aromatic L-amino acid decarboxylase activity in the kidney and increases dopamine. 1113 47

Nucleosides and nucleotides which are able to undergo covalent hydration in the aglycone ring system are potential inhibitors of the enzymes adenosine deaminase (ADA) and AMP deaminase, respectively. Calculations of the enthalpy of covalent hydration and of enzyme binding energy have been used to design new inhibitors of ADA. The ribosyl triazolotriazine 16, which was synthesized as a result of these calculations, exists predominantly as the covalent hydrate 18 in water and is a potent inhibitor of mammalian ADA (IC(50) 50 nM).
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PMID:Design and synthesis of inhibitors of adenosine and AMP deaminases. 1126 95

Among all fruits tested in vitro for their anti-platelet property, tomato had the highest activity followed by grapefruit, melon, and strawberry, whereas pear and apple had little or no activity. Tomato extract (20-50 microl of 100% juice) inhibited both ADP- and collagen-induced aggregation by up to 70% but could not inhibit arachidonic acid-induced platelet aggregation and concomitant thromboxane synthesis under similar experimental conditions. The anti-platelet components (MW <1000 Da) in tomatoes are water soluble, heat stable and are concentrated in the yellow fluid around the seeds. The active fractions were separated using gel filtration and HPLC. The aqueous fraction (110 000 xg supernatant) of tomatoes containing anti-platelet activity was subjected to gel filtration column chromatography (Biogel P2 column). The activity was fractionated into two peaks, peak-3 and peak-4 (major peak). Subsequently, peak-4 was further purified by HPLC using a reversed-phase column. NMR and mass spectroscopy studies indicated that peak F2 (obtained from peak 4) contained adenosine and cytidine. Deamination of peak F2 with adenosine deaminase almost completely abolished its anti-platelet activity, confirming the presence of adenosine in this fraction. In comparison, deamination of peak-4 resulted in only partial loss of inhibitory activity while the activity of peak-3 remained unaffected. These results indicate that tomatoes contain anti-platelet compounds in addition to adenosine. Unlike aspirin, the tomato-derived compounds inhibit thrombin-induced platelet aggregation. All these data indicate that tomato contains very potent anti-platelet components, and consuming tomatoes might be beneficial both as a preventive and therapeutic regime for cardiovascular disease.
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PMID:Effects of tomato extract on human platelet aggregation in vitro. 1145 56

By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis. Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E. coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg). Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10. PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10. PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines. Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation. Survival from sepsis was also improved when PNT was used as a posttreatment. These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes. These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.
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PMID:Inhibiting adenosine deaminase modulates the systemic inflammatory response syndrome in endotoxemia and sepsis. 1195 72

The nitrosative deaminations (37 degrees C, NaNO2, NaAc buffer, pH 3.7) of guanosine 1r in (18O)water (97.6%) and of [6-18O]-1r in normal water were studied. [6-(18)O]-1r was prepared from 2-amino-6-chloropurine riboside using adenosine deaminase. The reaction products xanthosine 3r and oxanosine 4r were separated by HPLC and characterized by LC/MS analysis and 13C NMR spectroscopy. The 18O-isotopic shifts on the 13C NMR signals were measured and allowed the identification of all isotopomers formed. The results show that oxanosine is formed via 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole, 5, and its 1,4-addition product 5-cyanoamino-4-imidazolecarboxylic acid, 6. This hydration of 5 to 6 leads to aromatization and greatly dominates over water addition to the cyanoimino group of 5 to form 5-guanidinyliden-4-oxomethylene-4,5-dihydroimidazole, 7. 5-Guanidinyl-4-imidazolecarboxylic acid, 8, the product of water addition to 6, is not involved.
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PMID:5-Cyanoimino-4-oxomethylene-4,5-dihydroimidazole and 5-cyanoamino-4-imidazolecarboxylic acid intermediates in nitrosative guanosine deamination: evidence from 18O-labeling experiments. 1530 70


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