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)

A unique seven-membered heterocyclic-ring inhibitor of adenosine deaminase was studied. One preparation of the compound inhibited replication of herpes simplex virus in the absence of adenine arabinoside. In this capacity, the minimal inhibitory concentration of deaminase inhibitor for herpes simplex virus type 1 (HSV-1), with 50 percent reduction of plaque-forming units as the end point, was 37.7 mug/ml. This activity compared favorably with the inhibitory activity of ara-hypoxanthine (34.1 mug/ml). Another preparation of deaminase inhibitor lacked antiviral activity. On the other hand, the adenosine deaminase inhibitor was active at a concentration of 0.009 mug/ml as a potentiator of the inhibition of HSV-1 by adenine arabinoside. The potentiation of adenine arabinoside by deaminase inhibitor is about 4,000 times more potent than the activity of the direct inhibitory effect on HSV-1. The nature of the possible contaminant of the preparation in question is unknown. Coformycin, another inhibitor of adenosine deaminase, had no antiviral activity in the absence of adenine arabinoside.
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PMID:Antiviral activity of an adenosine deaminase inhibitor: decreased replication of herpes simplex virus. 16 17

Deficiency of erythrocytic and lymphocytic adenosine deaminase (ADA) occurs in some patients with severe combined immunodeficiency disease (SCID). SCID with ADA deficiency is inherited as an autosomal recessive trait. ADA is markedly reduced or undetectable in affected patients (homozygotes), and approximately one-half normal levels are found in individuals heterozygous for ADA deficiency. The metabolism of purine nucleosides was studied in erythrocytes from normal individuals, four ADA-deficiency patients, and two heterozygous individuals. ADA deficiency in intake erythrocytes was confirmed by a very sensitive ammonia-liberation technique. Erythrocytic ADA activity in three heterozygous individuals (0.07,0.08, and 0.14 mumolar units/ml of packed cells) was between that of the four normal controls (0.20-0.37 mumol/ml) and the ADA-deficient patients (no activity). In vitro, adenosine was incorporated principally into IMP in the heterozygous and normal individuals but into the adenosine nucleotides in the ADa-deficient patients. Coformycin (3-beta-D-ribofuranosyl-6,7,8-trihydroimidazo[4,5-4] [1,3] diazepin-8 (R)-ol), a potent inhibitor of ADA, made possible incorporation of adenosine nucleotides in the ADA-deficient patients...
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PMID:Purine nucleoside metabolism in the erythrocytes of patients with adenosine deaminase deficiency and severe combined immunodeficiency. 94 48

Diethylaminoethyl-cellulose chromatography was used to separate the two isoenzymes of adenosine deaminase (EC3.5.4.4), adenosine deaminase1 (ADA1) and adenosine deaminase2 (ADA2), in human plasma. One hundred and fifteen purine base, nucleoside, and nucleotide analogs were tested as inhibitors of this partially purified preparation of ADA2. Coformycin and 2'-deoxycoformycin were by far the most potent inhibitors of this isoenzyme (apparent Ki values 20 and 19 nM, respectively). ADA2 was also inhibited by nebularine (apparent Ki 1.5 mM) but was resistant to the potent ADA1 inhibitor (+)-erythro-9(2-S-hydroxy-3-R-nonyl)adenine. alpha-D-Adenosine also inhibited ADA2, as did several halogenated purine and adenine base analogs. Structural requirements for the binding of purine analogs to ADA2 are presented which provide a general basis for the design of specific inhibitors of ADA2. Such inhibitors may be useful in studies designed to provide an understanding of the physiological role of ADA2 both in the normal state and in diseases such as human immunodeficiency virus-1 infection where levels in plasma are increased markedly.
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PMID:Structure-activity relationship of ligands of human plasma adenosine deaminase2. 204 51

(R)- and (S)-2'-deoxycoformycin, (R)-coformycin, and the corresponding 5'-monophosphates were compared as inhibitors of yeast AMP deaminase. The overall inhibition constants ranged from 4.2 mM for (S)-2'-deoxycoformycin to 10 pM for (R)-coformycin 5'-monophosphate, a difference of 3.8 x 10(8) in affinities. (R)-Coformycin, (R)-2'-deoxycoformycin 5'-monophosphate, and (R)-coformycin 5'-monophosphate exhibited both rapid and slow-onset inhibition. The S inhibitors and (R)-2'-deoxycoformycin exhibited classical competitive inhibition but no time-dependent onset of inhibition. The results indicate that the presence of the 2'-hydroxyl and 5'-phosphate and the R stereochemistry at the C-8 position of the diazepine ring are necessary for the optimum interaction of inhibitors with yeast AMP deaminase. This differs from the results for rabbit muscle AMP deaminase [Frieden C., Kurz, L. C., & Gilbert, H. R. (1980) Biochemistry 19, 5303-5309] and calf intestinal adenosine deaminase [Schramm, V. L., & Baker, D. C. (1985) Biochemistry 24, 641-646], in which a tetrahedral hydroxyl at C-8 in the R stereochemistry is sufficient for slow-onset inhibition with the coformycins. The results suggest that the transition state contains a tetrahedral carbon with the R configuration as a result of the direct attack of an oxygen nucleophile at C-6 of AMP. Slow-onset inhibition of yeast AMP deaminase is consistent with the mechanism [formula: see text] in which the combination of E and I is rapidly reversible. For these inhibitors, Ki varied by a factor of 3 x 10(3), and the overall inhibition constant (Ki*) varied by a factor of 2 x 10(5).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The rate constant describing slow-onset inhibition of yeast AMP deaminase by coformycin analogues is independent of inhibitor structure. 225 96

The 2',3'-dideoxynucleosides (ddNs) are currently undergoing clinical evaluation as antiretroviral agents in HIV-infected individuals. When phosphorylated, the ddNs (ddNTPs) function as chain-terminating substrate analogues with reverse transcriptase, thereby inhibiting HIV replication. These nucleoside analogues can also inhibit, by chain-terminating additions, the primitive lymphoid DNA polymerase, terminal deoxynucleotidyl transferase (TdT). To determine the effect of possible intracellular chain-terminating additions of ddNMPs by TdT, we exposed a series of TdT-positive and TdT-negative cell lines to 2',3'-dideoxyadenosine (ddA), a representative ddN. At ddA concentrations 25-fold higher than required for inhibition of HIV replication, progressive dose-related cytotoxicity was observed in the TdT-positive cell lines. This was accentuated by the adenosine deaminase inhibitor Coformycin (CF), presumably by enhancing the intracellular generation of ddATP from ddA. A central role of TdT in mediating the ddA/CF cytotoxicity was suggested by studies in a pre-B-cell line rendered TdT positive by infection with a TdT cDNA-containing retroviral vector. After a 48-hour continuous exposure period to 250 mumol/L ddA and 30 mumol/L CF, 30% cell death was observed in the TdT-negative parental line, whereas 90% cell death was observed in the TdT-positive daughter line. Exposure of fresh TdT-positive leukemic cells to ddA/CF for 72 hours ex vivo resulted in cytotoxicity (six cases of acute lymphocytic leukemia [ALL]) while not affecting TdT-negative acute leukemic cells (six cases). We conclude that ddA/CF selectively damages TdT-positive cells, presumably by chain-terminating additions of ddAMP, and that this may have therapeutic relevance in TdT-positive malignant disease.
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PMID:2',3'-Dideoxyadenosine is selectively toxic for TdT-positive cells. 283 1

The enzymatic inosine 5'-monophosphate assay described by Grassl [in, Methods of Enzymatic Analysis (H. U. Bergman, ed.), pp. 2168-2171, Academic Press, New York (1974)] is highly nonspecific, as ITP, ATP, ADP, AMP, and adenosine react stoichiometrically. The reactivity with the adenine derivatives is due to the tri- and diphosphatase activity of alkaline phosphatase (AP), coupled with adenosine deaminase (and possibly AMP deaminase) contamination of commercially available preparations of AP, purine-nucleoside phosphorylase, and/or xanthine oxidase. The inclusion of coformycin (0.05 microgram/ml), a potent inhibitor of these deaminases, completely eliminated the cross-reactivity. ITP, however, still reacted stoichiometrically due to the tri- and diphosphatase activity of AP. Meyer and Terjung [Amer. J. Physiol. 237 C111-C118 (1979)] introduced a modification of Grassl's procedure, substituting 5'-nucleotidase for AP. It has been found that this disallows reactivity with ATP, ADP, and ITP but that AMP and adenosine still react completely. Coformycin prevents this cross-reactivity. It is therefore recommended that the assay be carried out with 5'-nucleotidase (instead of AP) and coformycin, in order to achieve a more specific assay, and one more suitable for use with whole tissue extracts.
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PMID:An enzymatic inosine 5'-monophosphate assay of increased specificity. 298 81

Under conditions where 2'-deoxycoformycin is enzymatically phosphorylated by wheat shoot phosphotransferase to the 5'-phosphate in 15-20% yield, coformycin is a relatively poor substrate, and is phosphorylated only to the extent of less than or equal to 5%. However, chemical phosphorylation of coformycin by modifications of the Yoshikawa procedure led to isolation of coformycin-5'-phosphate in 20% overall yield. Coformycin-5'-phosphate was characterized by various criteria, including 1H NMR spectroscopy. Comparison of the spectrum with that of the parent nucleoside indicated that the nucleotide is predominantly, although not exclusively, in the conformation anti about the glycosidic bond. Like 2'-deoxycoformycin-5'-phosphate, coformycin-5'-phosphate was a feeble substrate of snake venom 5'-nucleotidase, and is hydrolyzed, quantitatively, at only 2% the rate for 5'-AMP. With 5'-AMP analogues as substrate, the 5'-phosphates of both coformycin and deoxycoformycin were poor inhibitors of the enzyme, with Ki values greater than 0.3 mM. The 5'-phosphates of both coformycin and deoxycoformycin do not significantly inhibit adenosine deaminase (Ki greater than 0.2 mM), but are potent inhibitors of adenylate deaminase (Ki less than or equal to 10(-9) M). Neither coformycin nor deoxycoformycin are inhibitors of mammalian purine nucleoside phosphorylase. The stabilities of coformycin, deoxycoformycin, and their 5'-phosphates, have been examined as a function of pH, and nature of the buffer medium. In particular, all exhibit instability in acid and neutral media, but are relatively stable in the vicinity of pH 9. Some biological aspects of the overall results are presented.
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PMID:Phosphorylation of coformycin and 2'-deoxycoformycin, and substrate and inhibitor properties of the nucleosides and nucleotides in several enzyme systems. 300 59

Ecto-5'-nucleotidase (ecto-5'-NU) of platelets was enhanced by concanavalin A (Con A). This effect of Con A was antagonized by alpha-methyl-D-mannose, a specific antagonist of Con A binding to glycoprotein. Coformycin, an adenosine deaminase inhibitor, did not change the effect of Con A on the ecto-5'-NU. Uptake of adenosine by platelets was not affected by Con A. It was suggested that the ecto-5'-NU of platelet might be a direct and primary site of action of Con A.
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PMID:Effect of concanavalin A on 5'-nucleotidase activity of rabbit blood platelets. 303 67

Extracts of Babesia divergens were examined for the enzymes which catalyse purine salvage. Adenosine deaminase (EC 3.5.4.4), guanine deaminase (EC 3.5.4.3), inosine phosphorylase (EC 2.4.2.1), purine phosphoribosyltransferases (EC 2.4.2.7, EC 2.4.2.8, EC 2.4.2.22) and nucleoside kinases (EC 2.7.1.15, EC 2.7.1.20, EC 2.7.1.73) were all detected at relatively high activities, whereas nucleotide interconverting enzymes were not detected. Coformycin and 4-amino-5-imidazolecarboxamide were found to be potent inhibitors of adenosine deaminase and guanine deaminase, respectively. The results suggest that B. divergens is capable of synthesizing purine nucleotides via two routes, one involving purine phosphoribosyltransferases and the other employing nucleoside kinases.
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PMID:Purine-metabolizing enzymes in Babesia divergens. 303 31

Coformycin, which is an inhibitor of adenosine deaminase, significantly inhibited in vitro blastogenic responses of human lymphocytes to both phytohaemagglutinin (PHA) and pokeweed mitogen (PWM), whereas blastogenic responses to bacterial lipopolysaccharide (LPS) were rather enhanced by the addition of coformycin. Blastogenic responses of lymphocytes to PHA and PWM were markedly suppressed by the addition of adenosine, which is a substrate of adenosine deaminase. Allopurinol, which is an inhibitor of xanthine oxidase, inhibited blastogenic responses of human lymphocytes to PHA, PWM, and bacterial LPS. Inosine (a substrate of purine nucleoside phosphorylase) and hypoxanthine (a substrate of xanthine oxidase) showed no or only a small effect on blastogenic responses of human lymphocytes. These results suggest that adenosine deaminase activity is associated with the T-cell response but not with the B-cell response and that the impaired T-cell response in adenosine deaminase deficiency is the result of intracellular retention of adenosine in T cells. The results also suggest that purine nucleoside phosphorylase or xanthine oxidase activity is associated with both T- and B-cell responses.
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PMID:Purine metabolic enzymes in lymphocytes. IV. Effects of enzyme inhibitors and enzyme substrates on the blastogenic responses of human lymphocytes. 392 75


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