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)

1. The pharmacological actions of the purine nucleotides beta-nicotinamide adenine dinucleotide (NAD), beta-nicotinamide adenine dinucleotide phosphate (beta-NADP), adenosine 5'-diphosphoribose (ADP-ribose), the vitamin nicotinamide and structural analogues of NAD and NADP were tested in the isolated perfused mesenteric arterial bed of the rat. Prejunctional effects of NAD were tested against sympathetic vasoconstriction at basal tone, and against sensory-motor vasodilatation at raised tone. 2. NAD and NADP had no vasoconstrictor action but were weak vasodilators of the raised-tone mesenteric arterial bed. A rank order of vasodilator potency of ADP >> ADP-ribose >> NADP > or = NAD = adenosine was observed. The P1-purinoceptor antagonist, 8-para-sulphophenyltheophylline (8-pST; 3 microM) inhibited vasodilator responses to NAD (pKB of 6.61 +/- 0.21, n = 7) and adenosine (pKB of 5.78 +/- 0.14, n = 6), but not those elicited by NADP, ADP and ADP-ribose. Nicotinamide, and analogues of NAD and NADP, namely nicotinamide-1,N6-ethenoadenine dinucleotide phosphate, beta-nicotinamide mononucleotide, nicotinamide hypoxanthine dinucleotide phosphate, nicotinamide hypoxanthine dinucleotide, nicotinamide guanine dinucleotide, and nicotinamide-1, N6-ethenoadenine dinucleotide had no vasoconstrictor or vasodilator actions (at doses of up to 50 nmol). 3. At basal tone, electrical field stimulation (EFS) (32 Hz, 1ms, 90 V, 5 s) at 2 min intervals elicited reproducible vasoconstrictor responses due to activation of sympathetic nerves. NAD and adenosine (10-100 microM) inhibited these responses in a concentration-dependent manner with similar potencies. Nicotinamide had no effect on sympathetic vasoconstriction at concentrations of up to 0.1 mM. Postjunctional effects of NAD (100 microM), as tested on constrictor responses to NA (5 nmol), accounted for approximately 60% inhibition at this concentration.4. In preparations in which tone had been raised with methoxamine (10-40 microM), EFS (8 Hz, 0.1ms,60 V, for 30 s) elicited vasodilatation due to activation of sensory-motor nerves. This vasodilatation was inhibited by NAD and adenosine (O.1-100 microM) in a similar concentration-dependent manner: pD2 values were 6.2 +/- 0.10 (n = 11) and 6.1 +/- 0.15 (n = 6) for NAD and adenosine respectively. Nicotinamide had no effect on sensory-motor vasodilatation at concentrations of up to 0.1 mM.5. Inhibition of sympathetic constriction by NAD and adenosine was antagonized by 8-pSPT (3 microM).Inhibitory effects of NAD and adenosine on sensory-motor vasodilatation were similarly antagonized by 8-pSPT (1 microM), pKB values were 6.72 +/- 0.21 for NAD and 6.36 +/- 0.22 for adenosine, resulting in parallel rightward shifts in the concentration-inhibitory effect curves.6. The adenosine deaminase inhibitor, pentostatin (1 microM), augmented the inhibitory effects of NAD and adenosine. Concentration-inhibitory effect curves for NAD and adenosine on sympathetic vasoconstriction and sensory-motor vasodilatation were shifted to the left without a change in the maximum.7. It is concluded that NAD can act as a modulator of sympathetic and sensory-motor transmission in rat mesenteric arteries via P1-purinoceptors possibly via direct actions but with a contribution of adenosine formed following breakdown of NAD or released pre- and/or post junctionally. Structure activity relationships of NAD, NADP, ADP and ADP-ribose showed that the P1-purinoceptor activity of NAD is abolished after removal of nicotinamide, or ribose plus nicotinamide, to yield the structurally-related ADP-ribose and ADP respectively, or when there is phosphorylation of the 2'-hydroxyl group of NAD to yield NADP.
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PMID:Modulation by nicotinamide adenine dinucleotide of sympathetic and sensory-motor neurotransmission via P1-purinoceptors in the rat mesenteric arterial bed. 759 21

Short-term hibernating myocardium is characterized by reduced contractile function during persistent ischemia, the recovery of metabolism over time, a recruitable inotropic reserve, and the lack of necrosis. The mechanisms underlying myocardial hibernation are unclear. The present study addressed the role of endogenous adenosine and that of activation of ATP-dependent potassium (KATP) channels. In 22 enflurane-anesthetized swine, coronary inflow was reduced to decrease regional myocardial work (W, measured by sonomicrometry) by 60-70% at 5 min of ischemia; this flow reduction has previously been shown to be compatible with the development of myocardial hibernation. Systemic hemodynamics, W, subendocardial blood flow (measured by microspheres), and the myocardial creatine phosphate content (measured by biopsies, mumol/g wet wt) were measured under control conditions and during 90 min of ischemia, with an intracoronary dobutamine infusion during the last 5 min of ischemia. The impact of endogenous adenosine was eliminated by infusion of intracoronary adenosine deaminase (ADA), and the impact of activation of KATP channels by glibenclamide. Creatine phosphate content recovered in the placebo-treated swine (n = 8, 3.8 +/- 1.9 to 5.8 +/- 2.0 mumol/g wet wt) as well as in swine receiving ADA (n = 7, 4.1 +/- 1.2 to 6.0 +/- 1.7 mumol/g wet wt) or glibenclamide (n = 7, 2.8 +/- 1.3 to 6.7 +/- 1.6 mumol/g wet wt) when ischemia was prolonged from 5 to 85 min. At the end of 90 min of ischemia, W increased during intracoronary dobutamine in all three groups to a comparable extent, and myocardial necrosis was absent in all three groups of swine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regional short-term myocardial hibernation in swine does not involve endogenous adenosine or KATP channels. 761 80

AMP deaminase (AMPD) catalyzes the hydrolytic deamination of AMP to IMP and NH3. This activity is represented throughout mammalian tissues and cells by at least three isoforms. Human AMPD cDNAs have been cloned and sequenced, leading to predictions that each isoform contains distinct amino-ends (N-terminal regions) in contrast to their highly conserved carboxyl-ends (C-terminal regions). Wild type, truncated, and chimeric human AMPD1 (isoform M) and AMPD2 (isoform L) cDNAs were expressed and the resultant activities partially characterized as a means to examine the role of divergent N-terminal regions in these polypeptides (residues 1-262 and 1-258 of isoforms M and L, respectively) on isoform-specific catalytic properties. Similar to activities purified from human tissues, in the presence of monovalent cation, wild type isoform M displayed hyperbolic kinetics in the presence and absence of ATP, whereas wild type isoform L exhibited allosteric activation in the presence of this nucleotide effector. Expression of both a chimeric M (5'-AMPD1)/L (3'-AMPD2) construct and one in which the N-terminal region of isoform L was deleted produced activities that were also allosterically regulated by ATP. However, no AMPD activity was detectable following expression of either a chimeric L (5'-AMPD2)/M (3'-AMPD1) construct or one in which the N-terminal region of isoform M had been deleted. The N-terminal region also affected the relative ability of each recombinant AMPD activity to deaminate substrate analogs modified in either the sugar or the phosphate, but not in the purine base, moieties of AMP. These combined data show (i) that isoform M, but not isoform L, absolutely requires its N-terminal region for proper function, (ii) that the C-terminal region of isoform L is responsible for allosteric activation by ATP, (iii) an effect of the N-terminal region on substrate-enzyme interaction, a contention that is discussed in context with available information regarding the related purine catabolic activity, adenosine deaminase.
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PMID:Divergent N-terminal regions in AMP deaminase and isoform-specific catalytic properties of the enzyme. 764 62

Immunoglobulins (IgG) from patients with Graves' disease increase inositol phosphate (IP) as well as cAMP production in rat thyroid FRTL-5 cells; IgGs from normal control subjects do not. Graves' IgG-and TSH-induced IP formation is inhibited by blocking TSH receptor (TSHR) antibodies from hypothyroid patients with primary myxedema, as is the cAMP response; this suggests that the Graves' IgG are acting through the TSHR to induce both the cAMP and phosphatidyl-inositol 4,5-biphosphate signal cascades in FRTL-5 thyroid cells as in cells with recombinant TSHR. Optimal conditions for measuring the Graves' IgG-induced IP increase include a NaCl-free Hanks' Balanced Salt Solution (HBSS) buffer system and a P1 purinergic receptor agonist; the action of each is additive. Optimization by NaCl-free HBSS is similar to that observed in cAMP assays and is specific for TSH or Graves' IgG; thus, NaCl-free HBSS did not affect ATP-induced, and actually inhibited norepinephrine-induced, IP production in FRTL-5 cells. The P1 purinergic receptor agonist acts via receptor cross-talk, which also allows further optimization of cAMP assays. Thus, adenosine deaminase improves Graves' IgG-induced cAMP production by removing adenosine from the medium. Although NaCl-free HBSS improved TSH- or Graves' IgG-induced IP and cAMP production in cells with recombinant TSHR; the modulatory action of phenylisopropyladenosine was lost.
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PMID:Receptor cross-talk can optimize assays for autoantibodies to the thyrotropin receptor: effect of phenylisopropyladenosine on adenosine 3',5'-monophosphate and inositol phosphate levels in rat FRTL-5 thyroid cells. 807 7

We investigated the effect of the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and coformycin on high-energy phosphate metabolism, tissue nucleotides and nucleosides, and recovery of contractile function in isolated, perfused guinea pig hearts. EHNA and coformycin (10 microM) improved postischemic recovery of contractile function approximately 85% and enhanced coronary flow rate in reperfused tissue approximately 40%. The protective effect of EHNA on recovery of contractile function was concentration dependent. Although adenosine (10 microM) increased coronary flow rate on reperfusion approximately twofold over vehicle, it failed to improve postischemic recovery of contractile function. EHNA and coformycin preserved cardiac ATP levels and increased endogenous tissue adenosine during ischemia. During reperfusion, these agents enhanced recovery of high-energy phosphates approximately twofold and potentiated adenosine release into the perfusate with concentration dependency. Furthermore, EHNA and coformycin reduced the extent of myocardial ischemia-reperfusion injury, as indicated by the approximately 55% reduction in creatine phosphokinase release. We conclude that inhibitors of adenosine deaminase attenuate myocardial ischemic injury and improve postischemic recovery of contractile function and metabolism through endogenous myocardial adenosine enhancement and ATP preservation.
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PMID:Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart. 823 12

Adenosine is recognised as an important regulator of myocardial function and coronary vascular tone in the ischaemic myocardium. It is produced by the enzymatic dephosphorylation of 5'-AMP by 5'-nucleotidase and the hydrolysis of SAH by SAH-hydrolase. 5'-Nucleotidase is thought to contribute to adenosine production aside from the accumulation of 5'-AMP in the ischaemic myocardium, while the hydrolysis of SAH plays a major role in adenosine production in the normoxic myocardium. 5'-Nucleotidase activity is reported to increase adenosine production through accumulation of ATP, ADP, H+, Mg2+ and inorganic phosphate during ischaemia. In addition, we have found that alpha 1 adrenergic receptors, activated in ischaemic hearts, increase both 5'-nucleotidase activity and adenosine production. Inactivation of adenosine deaminase and adenosine kinase may also contribute to adenosine production. On the other hand, the major role of endogenous adenosine is to increase coronary blood flow. This adenosine induced coronary vasodilatation is amplified by alpha 2 adrenoceptor stimulation. Adenosine induced vasodilatation is also enhanced by increasing H+ and opening ATP sensitive K+ channels, which occurs in the ischaemic myocardium. However, coronary vasodilatation is not the only effect of adenosine in the ischaemic myocardium. Stimulation of adenosine A2 receptors coupled to Gs proteins attenuates both free radical generation by activated leucocytes and aggregation of platelets. Adenosine A1 receptor activation coupled to G(i) proteins attenuates beta adrenoceptor mediated increases in myocardial contractility, Ca2+ influx into myocytes, and noradrenaline release from the presynaptic nerves. Any or all of these effects may attenuate ischaemic and reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of adenosine and its interaction with alpha adrenoceptor activity in ischaemic and reperfusion injury of the myocardium. 838 27

Exogenous adenosine triphosphate (ATP) added to brush-border membrane vesicles was rapidly degraded mainly to inosine according to the high ecto-nucleotidase activities in these vesicles. In the absence of phosphate, inosine was slowly transformed into hypoxanthine, and xanthine oxidase and dehydrogenase activities were not detected. The presence of ecto-adenosine deaminase and ecto-adenosine monophosphate (AMP) nucleotidase was shown. The ecto-adenosine deaminase was inhibited by deoxycoformycin and was also detected in rat renal brush-border membrane vesicles. Using orthovanadate, levamisole, and alpha, beta-methylene adenosine diphosphate as possible inhibitors, alkaline phosphatase was shown to be the main agent responsible for ecto-AMP nucleotidase activity. In pig renal basolateral membrane vesicles and in whole cell extracts from pig renal cortex, ecto-AMP nucleotidase was the limiting factor in ATP degradation. Comparing the ATP catabolism in the whole cell cortical extract with the catabolism in the same sample precleared of membranes, it was shown that ectonucleotidase activity is mainly bound to the membranous components. It is also shown that the whole cell extract of pig renal cortex has hypoxanthine phosphoribosyl transferase activity, and it seems probable that the rapid and specific formation of luminal inosine and its transport into the cell in competition with adenosine may start the purine salvage pathway through the synthesis of IMP from hypoxanthine.
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PMID:Adenine nucleotides and adenosine metabolism in pig kidney proximal tubule membranes. 840 44

Human cardiac valves are increasingly used in the reconstruction of ventricular outflow tracts and offer performance advantages over porcine and mechanical prostheses; the durability of these replacements has been associated with leaflet interstitial cell viability and a presumed sustained function after implantation. Preimplantation tissue preparation entails sequential steps that are potentially cytotoxic and may therefore affect functional cell survival at thaw. We defined the metabolic consequences of each interval using semilunar cusps from 118 porcine valves to model a homograft preparation with 40 minutes of fixed cadaveric (harvest) ischemia. Fifty-eight valves served as controls and were first processed according to standard cryopreservation protocol; nucleosides were extracted at the end of each step to differentiate independent contributions to high-energy phosphate depletion. Sixty simultaneously harvested leaflets were administered the nucleoside transport inhibitor p-nitrobenzy-thionosine (NBMPR) and the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) at procurement, to attempt adenosine salvage and restitution of processing-incurred adenine nucleotide losses. High-performance liquid chromatography was used to compare adenosine triphosphate, diphosphate, and monophosphate and diffusible nucleopurines of the control and EHNA/NBMPR-treated groups. Control results indicate that disruption of the adenosine triphosphate-diphosphate cycle occurs independently with antibiotic disinfection and cryopreservation. However, throughout all preparation steps, adenine nucleotides were maintained at harvest (baseline) concentrations in the EHNA/NBMPR valves. This suggests that salvage therapy may protect a significant number of cells from net high-energy phosphate catabolism. If, with further study, the durability of transplanted valves is concluded to benefit from retained leaflet interstitial cell viability, such enhancement of metabolic tolerance to the obligatory processing may facilitate functional recovery.
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PMID:Inhibition of adenosine deaminase and nucleoside transport. Utility in a model of homograft cardiac valve preimplantation processing. 850 37

Follicular oocytes of Xenopus laevis possess P1 purinoceptors where, seemingly, both adenosine (Ado) and ATP are agonists. The basis of ATP agonism at this P1 purinoceptor was investigated using electrophysiological and biochemical procedures. Ado and ATP activated an outward K+ current that reversed at -90 mV, was reduced by TEA and was inhibited by theophylline and 8-(p-sulphophenyl)-theophylline but not by suramin. Outward K+ current to ATP and Ado also was inhibited by alpha, beta-methylene ATP. The affinity constants for Ado and ATP were identical, although ATP was a partial agonist. The potency order of nucleosides/nucleotides was 5'-N-ethylcarboxamide- adenosine > Ado > AMP > CGS-21680 > beta, gamma-methylene ATP = ATP > ADP > R-N6 phenylisopropyl-adenosine, whereas 2-methylthioadenosine, ATP-O-(3-thiotriphosphate), uridine 5'-triphosphate and alpha, beta-methylene ATP were inactive. Outward K+ current to ATP and nondegradable Ado analogs was unaffected by adenosine deaminase (although this enzyme prevented Ado agonism), which suggests that ATP is not broken down to Ado before activating K+ channels. The activity of oocyte ecto-ATPase was determined by HPLC analysis of ATP breakdown and by the production of inorganic phosphate. Oocyte ecto-ATPase showed a low rate of ATP hydrolysis and was incapable of generating sufficient Ado/AMP to activate P1 purinoceptors. The results show that a P1 purinoceptor that is not typical of other known Ado receptors (and ATP receptors) is present in the follicle cell layer of Xenopus oocytes and represents a novel purinoceptor subtype where both Ado and ATP are agonists in their own right.
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PMID:A novel P1 purinoceptor activates an outward K+ current in follicular oocytes of Xenopus laevis. 855 61

We selected the common shrew (Sorex araneus) to generate the first insectivore gene map. Shrew-Chinese hamster and shrew- mouse somatic cell hybrid cells were constructed. When the 119 shrew-rodent clones were characterized, only shrew chromosomes were found to have segregated. A panel of hybrid clones was selected for gene assignment. The genes for hypoxanthine phosphoribosyl transferase (HPRT), glucose-6- phosphate dehydrogenase (G6PD), and malate dehydrogenase 1 (MDH1) were assigned to shrew Chromosome (Chr) de [which is the product of a tandem fusion between the 'original' mammalian X Chromosome (Chr) and an autosome], the gene for adenosine deaminase (ADA) and 6-phosphogluconate dehydrogenase se (PGD) to Chromosome jl, the gene for thymidine kinase (TK) to Chromosome hn, and the gene for lactate dehydrogenase (LDHA) to chromosome ik. Further studies in progress.
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PMID:Gene mapping in the common shrew (Sorex araneus; Insectivora) by shrew-rodent cell hybrids: chromosome localization of the loci for HPRT, TK, LDHA, MDH1, G6PD, PGD, and ADA. 859 34


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