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)

Deoxyadenosine has been implicated as the toxic metabolite causing profound lymphopenia in immunodeficient children with a genetic deficiency of adenosine deaminase (ADA), and in adults treated with the potent ADA inhibitor deoxycoformycin. However, the biochemical basis for deoxyadenosine toxicity toward lymphocytes remains controversial. The present experiments have examined in detail the sequential metabolic changes induced in nondividing human peripheral blood lymphocytes by incubation with deoxyadenosine plus deoxycoformycin, or with 2-chlorodeoxyadenosine (CdA), an ADA resistant deoxyadenosine congener with anti-leukemic and immunosuppressive properties. The lymphotoxic effect of deoxyadenosine and CdA required their phosphorylation, and was inhibited by deoxycytidine. As early as 4 h after exposure to the deoxynucleosides, strand breaks in lymphocyte DNA began to accumulate, and RNA synthesis decreased. These changes were followed by a significant fall in intracellular NAD levels at 8 h, a drop in ATP pools at 24 h, and cell death by 48 h. Incubation of the lymphocytes with 5 mM nicotinamide, a NAD precursor and an inhibitor of poly(ADP-ribose) synthetase, prevented NAD depletion. The nicotinamide treatment also rendered the lymphocytes highly resistant to deoxyadenosine and CdA toxicity, without altering dATP formation or the accumulation of DNA strand breaks. The poly(ADP-ribose) synthetase inhibitor 3-aminobenzamide exerted a similar although less potent effect. These results suggest that NAD depletion, probably triggered by poly(ADP-ribose) formation, is the principle cause of death in normal resting human lymphocytes exposed to deoxyadenosine plus deoxycoformycin, or to CdA.
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PMID:Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. 257 98

The human erythrocyte generates high-energy adenosine triphosphate by anaerobic glycolysis and cycles oxidized and reduced nicotinamide adenine dinucleotide phosphate by the aerobic pentose phosphate shunt pathway. Certain enzymopathies of the pentose phosphate shunt are associated with hemolysis resulting from oxidative denaturation of hemoglobin. Glucose-6-phosphate dehydrogenase deficiency, an X-chromosome-linked disorder, is the prototype of these diseases and is genetically and clinically polymorphic. Six enzymopathies of anaerobic glycolysis cause hemolytic anemia; lactate dehydrogenase deficiency does not. In 2,3-diphosphoglycerate mutase deficiency, 2,3-diphosphoglycerate is greatly reduced and asymptomatic polycythemia is noted. Pyrimidine-5'-nucleotidase deficiency, an enzymopathy of nucleotide metabolism, is characterized by intracellular accumulations of pyrimidine-containing nucleotides, marked basophilic stippling on the stained blood film, splenomegaly, and hemolysis. Lead inhibits the nucleotidase and an identical syndrome occurs during severe lead poisoning. Hemolysis also accompanies an unusual enzymopathy characterized by a 40- to 70-fold increase (not decrease) in adenosine deaminase activity.
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PMID:Hemolytic anemias and erythrocyte enzymopathies. 299 Feb 76

Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S-adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.
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PMID:Clinical response to deoxycoformycin in chronic lymphoid neoplasms and biochemical changes in circulating malignant cells in vivo. 326 92

The metabolic causes for immune impairment in patients with severe chronic inflammatory diseases have not been clearly defined. Recently, the overproduction of poly(ADP-ribose) in resting lymphocytes with unrepaired DNA strand breaks has been suggested to contribute to immune dysfunction in adenosine deaminase-deficient patients. Our experiments have determined to what extent DNA damage and poly(ADP-ribose) synthesis might also explain the impaired mitogen responsiveness of PBL exposed to toxic oxygen species. Treatment of normal resting human lymphocytes with xanthine oxidase and hypoxanthine dose-dependently induced DNA strand breaks and triggered the rapid synthesis of poly(ADP-ribose). Subsequently, NAD+ and ATP pools decreased precipitously. Lymphocytes exposed previously to the enzymatic oxidizing system did not synthesize DNA after stimulation with PHA. However, if the medium was supplemented with 3-aminobenzamide or nicotinamide, two compounds that inhibit poly(ADP-ribose) formation, cellular NAD+ and ATP pools were preserved, and the lymphocytes responded vigorously to a mitogenic challenge. Excessive poly(ADP-ribose) synthesis, provoked by DNA strand breakage, may represent a common pathway that connects the immunodeficiency syndromes associated with (a) exposure of lymphocytes to toxic oxygen species during chronic inflammatory states, (b) adenosine deaminase deficiency, and (c) certain DNA repair disorders.
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PMID:Lymphocyte dysfunction after DNA damage by toxic oxygen species. A model of immunodeficiency. 395 May 45

To investigate the problem of initiation in bacterial spore germination, we isolated, from extracts of dormant spores of Bacillus cereus strain T and B. licheniformis, a protein that initiated spore germination when added to a suspension of heat-activated spores. The optimal conditions for initiatory activity of this protein (the initiator) were 30 C in 0.01 to 0.04 m NaCl and 0.01 m tris(hydroxymethyl)aminomethane (pH 8.5). The initiator was inhibited by phosphate but required two co-factors, l-alanine (1/7 of K(m) for l-alanine-inhibited germination) and nicotinamide adenine dinucleotide (1.25 x 10(-4)m). In the crude extract, the initiator activity was increased 3.5-fold by heating the extract at 65 C for 10 min, but the partially purified initiator preparation was completely heat-sensitive (65 C for 5 min). Heat stability could be conferred on the purified initiator by adding 10(-3)m dipicolinic acid. A fractionation of this protein that excluded l-alanine dehydrogenase and adenosine deaminase from the initiator activity was developed. The molecular weight of the initiator was estimated as 7 x 10(4). The kinetics of germination in the presence of initiator were examined at various concentrations of l-alanine and nicotinamide adenine dinucleotide.
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PMID:Initiation of bacterial spore germination. 429 13

The purpose of this study was to investigate the possible importance of adenosine in cerebrocortical vasodilatation accompanying brain activation (epileptic seizures and direct electrical stimulation) and hypoxia (arterial hypoxia and cyanide poisoning of the brain cortex). In chloralose-anesthetized cats a circumscribed area of the brain cortex was treated with adenosine deaminase (Type III; Sigma), which potently deaminates adenosine to the nonvasoactive inosine. Cerebrocortical vascular volume and fluorescence of reduced nicotinamide adenine dinucleotide were measured in vivo by surface fluororeflectometry. The responses of small pial and intracortical vessels to brain activation and hypoxia were studied in brain cortices superfused with artificial (mock) CSF and 5 U/ml adenosine deaminase. It was found that superficially applied adenosine deaminase readily diffuses onto the brain cortex. Prolonged pretreatment of the brain cortices with 0.025 U/ml adenosine deaminase eliminated almost completely the vasodilative effect of 10(-7) mol/ml adenosine. The inhibitory effect of the enzyme on adenosine-induced cortical vasodilatation was specific, because 5 U/ml adenosine deaminase did not attenuate the vasodilative potency of 10(-8) mol/ml 2-chloroadenosine. Adenosine deaminase (5 U/ml) pretreatment of the brain cortices did not diminish the cerebrocortical vascular volume, which increased with arterial hypoxia, topical cyanide poisoning, and direct electrical stimulation. However, it slightly decreased the vasodilative effect of epileptic seizures. On the basis of these results, it seems very unlikely that adenosine is a critical factor in the control of cerebrovascular tone during arterial hypoxia and brain activation.
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PMID:Effect of topical adenosine deaminase treatment on the functional hyperemic and hypoxic responses of cerebrocortical microcirculation. 647 59

Human-Chinese hamster cell hybrids and a monoclonal antibody to human S-adenosylhomocysteine hydrolase were used to identify chromosome 20 as the location of the human gene for this enzyme. The gene for adenosine deaminase had previously been mapped to this chromosome. The activity of S-adenosylhomocysteine hydrolase is dependent in vivo on that of adenosine deaminase, since the substrates for the deaminase, adenosine and deoxyadenosine, respectively, inhibit and inactivate S-adenosylhomocysteine hydrolase in genetic or drug-induced adenosine deaminase deficiency. This functional dependence and the likelihood that S-adenosylhomocysteine hydrolase, a eukaryotic enzyme, arose later than adenosine deaminase, which occurs in prokaryotes as well as eukaryotes, suggest that the occurrence of their genes on the same chromosome may have evolutionary significance. In addition, the unusual capacity of S-adenosylhomocysteine hydrolase to form stable complexes with adenosine and its cofactor, nicotinamide adenine dinucleotide, suggest that evolution of its gene may have involved recombination of a portion of the adenosine deaminase gene with an adenine nucleotide domain-coding sequence of another preexisting gene.
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PMID:The human genes for S-adenosylhomocysteine hydrolase and adenosine deaminase are syntenic on chromosome 20. 707 34

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

Postmitotic sympathetic neurons are known to undergo a programmed cell death (apoptosis) when they are deprived of nerve growth factor (NGF) or treated with arabinofuranosyl nucleoside antimetabolites. Here we report the existence of a biochemical mechanism for the induction of neuronal death by an endogenous nucleoside in the presence of NGF. In support of such a mechanism we show that 2-deoxyadenosine (dAdo) induces apoptosis in chick embryonic sympathetic neurons supported in culture by NGF, excess K+, phorbol 12,13-dibutyrate, or forskolin. Neuronal death was related to a dramatic increase in the dATP content of sympathetic neurons exposed to dAdo (34.96 +/- 5.98 versus 0.75 +/- 0.16 pmol/micrograms protein in untreated controls, n = 9), implicating dATP in the toxicity. Supportive evidence for a central role of dATP was gained by inhibition of kinases necessary for phosphorylation of dAdo. 5'-Iodotubercidin in nanomolar concentrations completely and dose-dependently inhibited formation of dATP and also protected against toxicity of submillimolar concentrations of dAdo in sympathetic neurons. Although some of these actions of dAdo were remarkably similar to those reported for human lymphoid cells, several were uniquely different. For example, [3H]dAdo was not transported into neurons by the nucleoside transporter, and therefore inhibition of the transporter (dilazep, nitrobenzylthioinosine) did not prevent neurotoxicity by dAdo. Precursors of pyrimidine synthesis (2'-deoxycytidine, uridine) or NAD+ synthesis (nicotinamide) were ineffective in protecting sympathetic neurons against dAdo toxicity. Finally, inhibition of adenosine deaminase by deoxycoformycin or erythro-9-(2-hydroxy-3-nonyl) adenine did not potentiate the toxic effects of dAdo. Our results provide evidence for the first time that neuronal cells are as susceptible to nucleoside lethality as human lymphocytes are, and provide a new model to study the salvage pathway of deoxyribonucleosides in controlling neuronal populations through programmed cell death.
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PMID:Deoxynucleoside induces neuronal apoptosis independent of neurotrophic factors. 762 6

A previous study has shown that endogenous adenosine trapping during ischemia (by blocking adenine nucleoside transport and inhibiting adenosine breakdown) prevents myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reperfusion would similarly prevent myocardial stunning in the absence of entrapped adenosine. In both studies, a selective nucleoside transport blocker, p-nitrobenzyl-thioinosine, was used in combination with a potent adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, to entrap adenosine (preischemic treatment) or inosine (postischemic treatment) in an in vivo canine model of reversible global ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrometry) to monitor left ventricular performance from the relationship between stroke work and end-diastolic length as a sensitive and load-independent index of contractility. Hearts of animals supported by cardiopulmonary bypass were subjected to 30 minutes of normothermic global ischemia and 60 minutes of reperfusion. Saline solution containing the pharmacologic agents were infused into the bypass circuit before ischemia (group 1) or during reperfusion (group 2). Control group (group 3) received saline before and after ischemia. Myocardial biopsy specimens were obtained before, during, and after ischemia, and levels of adenine nucleotides, nucleosides, oxypurines, and the oxidized form of nicotinamide-adenine dinucleotide were determined. Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-thioinosine (p < 0.05 versus control group). Myocardial adenosine triphosphate was depleted by 50% in all groups at the end of ischemia. Adenosine triphosphate recovered during reperfusion only in the group that was treated with inhibitors before ischemia (group 1). At the end of ischemia, adenosine levels were low (< 10% of total nucleosides) in the control group (group 3) and in the group treated only after ischemia (group 2). A high level of adenosine (> 90% of total nucleosides) was present in group 1. We infer that selective pharmacologic blockade of nucleoside transport, only after ischemic injury, accelerated functional recovery during reperfusion, even without trapping of endogenous adenosine during ischemia and without adenosine triphosphate recovery during reperfusion. Recovery of myocardial adenosine triphosphate required preischemic treatment and adenosine entrapment during ischemia and reperfusion. Therefore, nucleoside trapping may be used to prevent reperfusion-mediated injury after reversible ischemic injury.
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PMID:Nucleoside trapping during reperfusion prevents ventricular dysfunction, "stunning," in absence of adenosine. Possible separation between ischemic and reperfusion injury. 804 Nov 75


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