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)

Adenosine deaminase, which catalyzes the irreversible hydrolytic deamination of adenosine nucleosides to inosine nucleosides and ammonia, is a key enzyme in purine metabolism and lymphoid development. The X-ray structures of murine adenosine deaminase with bound potent inhibitors (Ki values approximately 10(-13) M) (8R)-hydroxyl-2'-deoxycoformycin (pentostatin), a transition state analogue, and (6S)-hydroxyl-1,6-dihydropurine riboside, a reaction coordinate analogue, have been determined and refined to resolutions of 2.6 and 1.95 A, respectively. Crystals of both complexes were obtained at pH 7, where the enzyme is fully active, in an identical space group with the asymmetric unit containing four molecules. In addition to the very high degree of similarity between the four independent molecules in each complex structure, there is also considerable structural similarity of the complex with the dihydropurine riboside with that of an identical complex previously determined at pH 4.2 where the enzyme is 20% active. The interactions between the enzyme and the two analogues are extremely similar. These include the coordination of the 8R- or 6S-hydroxyl group of the analogues to the Zn2+ which mainly contributes to the strong potency and very high degree of stereospecificity of inhibition by these analogues. The interactions are further indicative of the structural and chemical requirements of substrates. These structures and recent site-directed mutagenesis have further shed light on the catalytic mechanism of the enzyme.
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PMID:Complexes of adenosine deaminase with two potent inhibitors: X-ray structures in four independent molecules at pH of maximum activity. 962 83

Synthesis of (R)-(-)- and (S)-(+)-synadenol (1a and 2a, 95-96% ee) is described. Racemic synadenol (1a + 2a) was deaminated with adenosine deaminase to give (R)-(-)-synadenol (1a) and (S)-(+)-hypoxanthine derivative 5. Acetylation of the latter compound gave acetate 6. Reaction with N, N-dimethylchloromethyleneammonium chloride led to 6-chloropurine derivative 7. Ammonolysis furnished (S)-(+)-synadenol (2a). Absolute configuration of 1a was established by two methods: (i) synthesis from (R)-methylenecyclopropanecarboxylic acid (8) and (ii) X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. Racemic methylenecyclopropanecarboxylic acid (10) was resolved by a modification of the described procedure. The R-enantiomer 8 was converted to ethyl ester 13 which was brominated to give vicinal dibromides 14. Reduction with diisobutylaluminum hydride then furnished alcohol 15 which was acetylated to the corresponding acetate 16. Alkylation-elimination procedure of adenine with 16 yielded acetates 17 and 18. Deprotection with ammonia afforded a mixture of Z- and E-isomers 1a and 19 of the R-configuration. Comparison with products 1a and 2a by chiral HPLC established the R-configuration of (-)-synadenol (1a). These results were confirmed by X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. The latter forms a pseudosymmetric dimer with adenine-adenine base pairing in the lattice with the nucleobase in an anti-like conformation. Enantiomers 1a and 2a exhibit varied enantioselectivity toward different viruses. Both enantiomers are equipotent against human cytomegalovirus (HCMV) and varicella zoster virus (VZV). The S-enantiomer 2a is somewhat more effective than R-enantiomer 1a in herpes simplex virus 1 and 2 (HSV-1 and HSV-2) assays. By contrast, enantioselectivity of antiviral effect is reversed in Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1) assays where the R-enantiomer 1a is preferred. In these assays, the S-enantiomer 2a is less effective (EBV) or devoid of activity (HIV-1).
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PMID:(R)-(-)- and (S)-(+)-Synadenol: synthesis, absolute configuration, and enantioselectivity of antiviral effect. 985 93

Of the human salvage enzymes that deaminate ribonucleosides, two--cytidine deaminase and adenosine deaminase--have been found particularly useful for diagnostic purposes. In humans, no enzymes are present that can directly deaminate the bases of these ribonucleosides. Indeed, the only enzyme present that can directly deaminate a base is guanine deaminase, and the diagnostic usefulness of this enzyme has been well documented. The aim of this study is to identify the origin of the ammonia formed when human sera and tissue extracts are incubated with buffered guanosine, and to clarify whether the ammonia comes from the deamination of guanosine by guanosine deaminase or is produced as a result of deamination of guanine formed as a breakdown product of guanosine by purine nucleoside phosphorylase (PNP). Apparent deamination of guanosine by guanosine deaminase in human sera and tissue extracts was found to be due to two enzymes acting in tandem when the products of the reaction were examined by HPLC. The ribose was first removed from guanosine by PNP to form guanine, which was then deaminated to xanthine by guanine deaminase.
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PMID:Guanosine deaminase in human serum and tissue extracts--a reappraisal of the products. 1472 35

Serum activity of the adenosine deaminase (ADA) isozyme, ADA2, has been reported to be elevated during various disease states. Macrophages have been suggested as the cellular source of extracellular ADA activity because they are one of the only cell types in which intracellular ADA2 activity has been measured, but extracellular secretion has never been demonstrated. Rat primary peritoneal macrophages (PPMs) and peripheral blood monocytes (PBMs) were harvested and incubated for 18 h in RPMI supplemented with horse serum. PPM and PBM lysates were assayed for intracellular ADA activity (ammonia production). In vitro and in vivo extracellular ADA activities were measured in media and rat serum, respectively. Activity of ADA1 was confirmed by selective inhibition with erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA). ADA2 activity was inhibited by 2'-deoxycoformcin only, and was increased at a low pH (6.5). Activity of both ADA isozymes was found in PPMs and PBMs, and their media. In a separate group of rats, peritonitis was induced by ip insertion of 400 mg/kg caecal slurry. PPMs were harvested 24 h later and incubated for 18 h. In PPMs from rats with peritonitis both isozymes were elevated by a similar proportion. In contrast, media from these PPMs had a lower ADA1 and a higher ADA2 activity compared to PPMs from nonseptic rats. This resulted in a greater proportion of ADA2 in media. The isozyme proportions in serum from septic rats more closely resembled that of the PPM media. The response of PBM was small relative to that of PPM. These results suggest that macrophages are a significant source of extracellular ADA isozymes, the activity of which increases during an inflammatory response. Because extracellular isozymes profiles differ from cellular concentrations, the data also suggest differential release of each isozyme from PPMs.
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PMID:Macrophages are a source of extracellular adenosine deaminase-2 during inflammatory responses. 1537

Adenosine kinase is an enzyme catalyzing the reaction: adenosine + ATP --> AMP + ADP. We studied some biochemical properties not hitherto investigated and demonstrated that the reaction can be easily reversed when coupled with adenosine deaminase, which transforms adenosine into inosine and ammonia. The overall reaction is: AMP + ADP --> ATP + inosine + NH(3). The exoergonic ADA reaction shifts the equilibrium and fills the energy gap necessary for synthesis of ATP. This reaction could be used by cells under particular conditions of energy deficiency and, together with myokinase activity, may help to restore physiological ATP levels.
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PMID:A kinetic study of the rat liver adenosine kinase reverse reaction. 1860 May 55

The pathogenetic mechanisms of laryngeal airway hyperreactivity (LAH) in patients with extraesophageal reflux are unclear. We recently reported that a laryngeal acid-pepsin insult produces LAH that is mediated through sensitization of the capsaicin-sensitive laryngeal afferent fibers by reactive oxygen species (ROS) in rats. Since ROS may promote the release of ATP from cells, we hypothesized that activation of P2X purinoceptors by ATP subsequent to an increase in ROS induces LAH in an inflamed larynx that has been insulted by acid-pepsin or H(2)O(2) (a major type of ROS). The larynxes of 208 anesthetized rats were functionally isolated while the animals breathed spontaneously. Ammonia vapor was delivered into the larynx to measure laryngeal reflex reactivity. Laryngeal insult with acid-pepsin or H(2)O(2) produced LAH with similar characteristics. The H(2)O(2)-induced LAH was prevented by laryngeal pretreatment with dimethylthiourea (a hydroxyl radical scavenger), suggesting a critical role for ROS. The LAH induced by both insults were completely prevented by ATP scavengers (a combination of apyrase and adenosine deaminase) or a P2X receptor antagonist (iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate). Laryngeal application of a P2X receptor agonist (alpha,beta-methylene-ATP) also produced LAH. An insult with either acid-pepsin or H(2)O(2) similarly promoted an increase in the levels of ATP, lipid peroxidation, and inflammation in the larynx. Our findings suggest that laryngeal insult with acid-pepsin or H(2)O(2) induces inflammation and produces excess ROS in the rat's larynx. The latter may in turn promote the release of ATP to activate P2X receptors, resulting in sensitization of capsaicin-sensitive laryngeal afferent fibers and LAH.
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PMID:Role of ATP in the ROS-mediated laryngeal airway hyperreactivity induced by laryngeal acid-pepsin insult in anesthetized rats. 1924 55

Cytosolic enzymes AMP deaminase and adenosine deaminase (ADA) catalyze AMP and adenosine deamination, constitute rate-limiting steps of adenine nucleotide catabolism and play important roles in cellular energy metabolism. In this study, AMP deaminase and ADA activities of rat liver, neocortex, cerebellum, striatum and hippocampus were investigated in acute ammonia intoxication and subacute CCl(4)-induced hepatitis. Activities of both AMP deaminase and ADA in the liver were elevated by 2.4-4.2-fold (p<0.0001) in both models of hepatotoxic injury as compared with controls. In acute hyperammonemia activities of AMP, deaminase and ADA increased by 46-59% (p<0.02) in the neocortex and did not change in the striatum. In the hippocampus of hyperammonemic rats, only AMP deaminase activity was increased by 48% (p=0.0004), and in the cerebellum only ADA activity was increased significantly (by 26%, p<0.05). The adenylate pool size and energy charge were greatly reduced in the neocortex of hyperammonemic rats. Results suggested that two parallel pathways of AMP breakdown, including AMP deaminase and ADA, respectively, are up-regulated under pathological conditions, probably in order to overcome compensatory synthesis of adenylates, to ensure prompt adenylate pool depletion and reduce the adenylate energy charge in liver and selected brain regions.
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PMID:AMP deaminase and adenosine deaminase activities in liver and brain regions in acute ammonia intoxication and subacute toxic hepatitis. 1990 Apr 20

We studied the effect of acute ammonia poisoning and CCl4-induced subacute hepatitis on activities of AMP deaminase and adenosine deaminase in rat liver. Both models of liver failure were accompanied by an increase in activities of AMP deaminase and adenosine deaminase in the cytoplasmic fraction of the liver (by 2.4-4.2 times compared to the control). A direct correlation was found between activities of AMP deaminase and adenosine deaminase. We believe that two parallel pathways of AMP degradation are activated simultaneously, which leads to rapid depletion of adenylate reserves under pathological conditions.
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PMID:Activation of AMP deaminase and adenosine deaminase in the liver during ammonia poisoning and hepatitis. 2116 Oct 45

L-arginine is conditionally essetcial amino acid, required for normal cell growth, protein synthesis, ammonia detoxification, tissue growth and general performance, proposed in the treatment of men sterility and prevention of male impotence. The aim of the present paper was to estimate the activity of the enzymes of adenine nucleotide metabolism: 5'-nucleotidase (5'-NU), adenosine deaminase (ADA), AMP deaminase, and xanthine oxidase (XO), during dietary intake of L-arginine for a period of four weeks of male Wistar rats. Adenosine concentration in tissues is maintained by the relative activities of the adenosine-producing enzyme, 5'-NU and the adenosine-degrading enzyme-ADA adenosine deaminase. Dietary L-arginine intake directed adenine nucleotide metabolism in liver, kidney, and testis tissue toward the activation of adenosine production, by increased 5'-NU activity and decreased ADA activity. Stimulation of adenosine accumulation could be of importance in mediating arginine antiatherosclerotic, vasoactive, immunomodulatory, and antioxidant effects. Assuming that the XO activity reflects the rate of purine catabolism in the cell, while the activity of AMP deaminase is of importance in ATP regeneration, reduced activity of XO, together with the increased AMP-deaminase activity, may suggest that adenine nucleotides are presumably directed to the ATP regenerating process during dietary L-arginine intake.
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PMID:L-arginine intake effect on adenine nucleotide metabolism in rat parenchymal and reproductive tissues. 2262 85

Pulmonary tuberculosis is the India's biggest health problem especially in rural areas. A quick and dependable investigation is absolutely essential. Adenosine deaminase was estimated from the biological fluids (ascitic/pleural/CSF) with the help of the kit obtained from Tulip India Pvt Ltd. The method is based on the principle of Galati & Giusti colorimetric method. The method is simple, inexpensive and results are also reproducible. Elevation of adenosine deaminase has shown high specificity in all biological fluids. As the estimation principle is based on synthesis of ammonia so there is limitation of the procedure when the site is kidney. Similarly if the site is skin, as fluid cannot be collected from the site, adenosine deaminase estimation is also not possible.
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PMID:Adenosine deaminase--the non-invasive marker of tuberculosis. 2302 24


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