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)

2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. The complex between adenosine deaminase and 2'-chloropentostatin dissociated with a half-life of approximately 3 hr, compared with 68 hr for the complex between adenosine deaminase and pentostatin. 2'-Chloropentostatin, at concentrations up to 10 micromolar, did not cause significant inhibition of growth of WI-L2 human B-cell lymphoblasts, or of CCRF-CEM human T-cell lymphoblasts in culture. However, it greatly potentiated the inhibitory potency of adenosine, 2'-deoxyadenosine, or arabinosyladenine towards these cell lines. This potentiating effect was equipotent for 2'-chloropentostatin and pentostatin. T-cells (CCRF-CEM) were much more sensitive to the inhibitory effect of combinations of adenosine or 2'-deoxyadenosine with 2'-chloropentostatin or pentostatin than were B-cells (WI-L2). Pentostatin and 2'-chloropentostatin had no significant antitumor activity against mouse leukemia L1210 in vivo. However, these adenosine deaminase inhibitors, at nontoxic doses, greatly potentiated the antitumor activity of ara-A 5'-phosphate. 2'-Chloropentostatin was somewhat more active in this regard than was pentostatin.
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PMID:The biochemical pharmacology of (2'-R)-chloropentostatin, a novel inhibitor of adenosine deaminase. 243 5

This paper reports the detection of five inherited disorders of purine and one of pyrimidine metabolism using intact red blood cells (RBCs) and compares the findings with those from RBC lysate activity. Two different phosphate levels (1 and 18 mmol L-1 Pi) were used to evaluate endogenous PP-ribose-P levels and their generation by PP-ribose-P synthetase. The importance of this dual approach is demonstrated by the following evidence: (a) Six out of eight patients with no detectable hypoxanthine-guanine phosphoribosyltransferase (HGPRT) RBC lysate activity had up to 25% of normal activity in their intact RBCs. Two Lesch-Nyhan patients showed no detectable activity in intact or lysed RBCs. (b) RBC lysates from two heterozygotes for adenosine deaminase (ADA) deficiency also showed no detectable activity, but up to 60% of normal activity using intact RBCs. (c) The existence of an aberrant enzyme in a kindred with a superactive PP-ribose-P synthetase was evident from the fact that intact RBCs failed to respond normally to phosphate activation, despite normal HGPRT and adenine phosphoribosyltransferase (APRT) RBC lysate activity. (d) Raised endogenous PP-ribose-P levels in intact RBCs were demonstrable only in purine nucleoside phosphorylase (PNP) and HGPRT deficiency; levels were normal in APRT deficiency and hereditary oroticaciduria (OPRT/ODC) deficiency. The results indicate that diagnosis from RBC lysate activity alone may be misleading. Intact RBC studies clearly provide a better indication of the functional capacity of the enzyme in vivo. They also show a closer correlation with the clinical phenotype and allow further insight into the associated biochemical abnormalities in some cases.
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PMID:Use of intact erythrocytes in the diagnosis of inherited purine and pyrimidine disorders. 244 57

The metabolic pathway of inositol phospholipids represents a series of synthetic and hydrolytic reactions with inositol as a by-product. Hence, the rate of [3H]inositol release from prelabeled phospholipids can be used as a reflection of activity of this pathway. In the frog sympathetic ganglion prelabeled with [3H]inositol, we studied the effect of synaptic activity (orthodromic stimulation) on release of 3H-label into the medium. This release was interpreted as [3H]inositol release. The value was low at rest and increased significantly by 32% during orthodromic stimulation (20 Hz for 5 min). However, on cessation of the stimulation, [3H]inositol release increased rapidly by 148% and remained elevated for at least 45 min. This increase in [3H]inositol release during and after the stimulation period was reduced by suffusion of the ganglia with adenosine. We hypothesized that synaptic activation releases a long-lasting stimulatory agonist and a short-lasting inhibitory (adenosine) agonist or agonists affecting [3H]inositol release. To demonstrate the presence of a stimulatory agonist, two sympathetic ganglia were used. One was prelabeled with [3H]inositol, and the other was not. The two ganglia were placed together in a 5-microliter droplet of Ringer's solution containing atropine. Orthodromic stimuli applied to the nonlabeled ganglion elicited release of [3H]inositol from the nonstimulated ganglion. To test whether the adenosine formed during orthodromic stimulation inhibits [3H]inositol release, we destroyed endogenous adenosine by suffusion of the ganglia with adenosine deaminase during the stimulation period. We found that adenosine deaminase induced large increases in [3H]inositol release during the stimulation period, in contrast to an increase seen only during the poststimulation period when adenosine deaminase was omitted. Because [3H]inositol release is assumed to parallel changes in content of inositol phosphates, we anticipated no changes of the levels of these compounds during orthodromic stimulation. However, measurements showed that levels of inositol phosphates and inositol phospholipids were all elevated except for phosphatidylinositol 4-phosphate. On termination of the stimulus, they remained elevated, with a further increase in levels of inositol trisphosphate and phosphatidylinositol 4-phosphate. We conclude that endogenous adenosine inhibits [3H]inositol release, possibly by modulating several of the steps of the inositol phospholipid pathway.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inositol phospholipid metabolism during and following synaptic activation: role of adenosine. 278 60

Different phosphate concentrations were studied for their effect on the degradation of adenosine by rat liver homogenates. It is shown that phosphate considerably inhibits the phosphoribomutase reaction without a significant effect on adenosine deaminase and purine nucleoside phosphorylase activities, that leads to the ribose-1-phosphate accumulation and to the disturbance of nucleoside utilization in reactions of the pentose phosphate pathway. It is supposed that the inhibition of the phosphoribomutase reaction by phosphate is important for regulation of nucleoside and nucleotide formation in a cell.
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PMID:[Phosphate inhibition of the conversion of ribose-1-phosphate--a product of purine nucleoside phosphorylase splitting in the phosphoribomutase reaction]. 282 85

Our recent studies have indicated that release of ATP/ADP from platelets causes enhanced O2-. responses in stimulated neutrophils. The current investigations were designed to provide further details of this phenomenon, to determine the structure-function correlates of the adenine compounds, and to assess if the results might be explained by the formation of a single metabolic product of ATP. ATP, ADP, AMP and adenosine enhanced O2-. responses of rat neutrophils stimulated with immune complexes or formyl chemotactic peptide (FMLP) but had no effect on responses of phorbol ester-stimulated neutrophils. Similar results were obtained in human neutrophils stimulated with immune complexes; when FMLP was the agonist, the results were divergent: ATP and ADP enhanced the responses, whereas AMP and adenosine were inhibitory. In structure-function studies, hydrolytically resistant forms of ATP (and other adenine nucleotides) containing blocked or cross-linked phosphate groups were active, suggesting that hydrolysis of these compounds to a common metabolic product is not required for their effects on O2-. responses. In contrast, other chemical modifications of the ribose ring or adenine base of ATP resulted in greatly diminished activity. To further pursue the question of whether metabolism of the adenine compounds via the adenosine pathway was related to the observed effects on O2-. responses, addition to rat neutrophils of inhibitors of adenosine deaminase, S-adenosyl homocysteine hydrolase, or xanthine oxidase failed to reproduce or augment the enhancement effects of the adenine compounds on O2-. responses, suggesting that metabolism of the adenine compounds to a common product may not be a requirement for the observed effects. Although the manner by which the adenine compounds affect O2-. responses is not known, the data suggest that adenosine and adenine nucleotides have important regulatory effects on oxygen radical responses of stimulated neutrophils.
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PMID:Regulatory effects of adenosine and adenine nucleotides on oxygen radical responses of neutrophils. 283 59

We examined the mechanism by which adenosine inhibits prolactin secretion from GH3 cells, a rat pituitary tumour line. Prolactin release is enhanced by vasoactive intestinal peptide (VIP), which increases cyclic AMP, and by thyrotropin-releasing hormone (TRH), which increases inositol phosphates (IPx). Analogues of adenosine decreased prolactin release, VIP-stimulated cyclic AMP accumulation and TRH-stimulated inositol phospholipid hydrolysis and IPx generation. Inhibition of InsP3 production by R-N6-phenylisopropyladenosine (R-PIA) was rapid (15 s) and was not affected by the addition of forskolin or the removal of external Ca2+. Addition of adenosine deaminase or the potent adenosine-receptor antagonist, BW-A1433U, enhanced the accumulation of cyclic AMP by VIP, indicating that endogenously produced adenosine tonically inhibits adenylate cyclase. The potency order of adenosine analogues for inhibition of cyclic AMP and IPx responses (measured in the presence of adenosine deaminase) was N6-cyclopentyladenosine greater than R-PIA greater than 5'-N-ethylcarboxamidoadenosine. This rank order indicates that inhibitions of both cyclic AMP and InsP3 production are mediated by adenosine A1 receptors. Responses to R-PIA were blocked by BW-A1433U (1 microM) or by pretreatment of cells with pertussis toxin. A greater amount of toxin was required to eliminate the effect of R-PIA on inositol phosphate than on cyclic AMP accumulation. These data indicate that adenosine, in addition to inhibiting cyclic AMP accumulation, decreases IPx production in GH3 cells, possibly by directly inhibiting phosphoinositide hydrolysis.
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PMID:Regulation of GH3-cell function via adenosine A1 receptors. Inhibition of prolactin release, cyclic AMP production and inositol phosphate generation. 284 12

The 5'-deoxy-5'-iodo-substituted analogs of adenosine and inosine are cytotoxic to tumor cells that have high activities of 5'-methylthioadenosine phosphorylase and purine nucleoside phosphorylase, respectively (Savarese, T.M., Chu, S-H., Chu, M.Y., and Parks, R. E., Jr. (1984) Biochem. Pharmacol. 34, 361-367). 5-Iodoribose 1-phosphate (5-IRib-1-P), the common intracellular metabolite of these 5'-iodonucleosides, has been synthesized enzymatically from 5'-deoxy-5'-iodoadenosine via adenosine deaminase from Aspergillus oryzae and human erythrocytic purine nucleoside phosphorylase. The purification and chemical properties of 5-IRib-1-P are described. The analog sugar phosphate inhibited purine nucleoside phosphorylase from human erythrocytes, phosphoglucomutase from rabbit muscle, and 5'-methylthioadenosine phosphorylase from Sarcoma 180 cells with Ki values of 26, 100, and 9 microM, respectively. Enzymes that react with 5-phosphoribosyl 1-pyrophosphate (P-Rib-PP), P-Rib-PP amidotransferase, hypoxanthine-guanine phosphoribosyltransferase, adenine phosphoribosyltransferase, and orotate phosphoribosyltransferase-orotidylate decarboxylase from extracts of Sarcoma 180 cells, were inhibited with Ki values of 49, 465, 307, and 275 microM, respectively. 5-IRib-1-P had no effect on P-Rib-PP synthetase. Since the Ki values of the analog sugar phosphate for 5'-methylthioadenosine phosphorylase and P-Rib-PP amidotransferase are much lower than the Km values of the natural substrates, Pi or P-Rib-PP which are reported to be present at nonsaturating concentrations under physiological conditions, these enzymes could be significantly inhibited by 5-IRib-1-P in intact cells.
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PMID:5-Iodoribose 1-phosphate, an analog of ribose 1-phosphate. Enzymatic synthesis and kinetic studies with enzymes of purine, pyrimidine, and sugar phosphate metabolism. 293 89

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

Many of the conventional agarose phosphoglucomutase (PGM) subtyping systems presently in use fail to provide a good separation between the 1 + and 2- bands as well as the 2+ band and the more anodic moving bands. Use of a 1-mm-thick gel composed of 1% ISO GEL (FMC Corp.) and phosphate-citric acid gel and tank buffers with a pH of 5.3 provided exceptionally good separation between all four of the major subtyping bands. The additional criteria for this procedure is a voltage of 21 V/cm and a run time of 4 h. Utilization of this procedure using case samples of varied ages proved the reliability of the procedure. Also examined were the effects of several reducing agents on the enzyme band patterns and the use of this system for the simultaneous determinations of the adenosine deaminase (ADA), erythrocyte acid phosphatase (EAP), and adenylate kinase (AK) enzyme phenotypes.
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PMID:Simultaneous electrophoretic determination of phosphoglucomutase subtypes, adenosine deaminase, erythrocyte acid phosphatase, and adenylate kinase enzyme phenotypes. 299 75

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


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