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Query: UNIPROT:P06889 (Mol)
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The incorporation of the radiolabeled adenosine analogs tubercidin, formycin A, 9-deaza-adenosine, and adenine arabinoside into nucleotides of Schistosoma mansoni schistosomules was studied in vitro. Of the four analogs, only tubercidin and formycin A were incorporated into the nucleotide pool, at rates respectively one-tenth and one-fiftieth the rate of adenosine incorporation. Tubercidin inhibited schistosomule motility in vitro with an approximate IC50 value of 1 microM, whereas formycin A exerted no visible effect even when more of it than of tubercidin was incorporated into the nucleotides and nucleic acids. Formycin A thus acts like a nontoxic adenosine analog. 7-Deaza-adenine, the purine base of tubercidin, was not incorporated into nucleotides. 7-Deaza-adenine, 9-deaza-adenosine, and adenine arabinoside all had no effect on schistosomule motility at concentrations up to 100 microM. Formycin A blocked the incorporation of tubercidin and of adenosine with equal effectiveness, as did p-nitrobenzyl-6-mercaptopurine ribonucleoside, a specific inhibitor of nucleoside transport in many mammalian cells. Thus, formycin A, tubercidin, and adenosine appear to have a common mechanism of cellular uptake. The significant levels of adenosine phosphorylase and adenine phosphoribosyl transferase activity found in schistosomule extracts suggests that most of the transported adenosine is converted to adenine before conversion to AMP. The levels of adenosine kinase and tubercidin kinase, while low, can more than account for the rate of tubercidin incorporated into intact schistosomules. The kinase(s) may also represent a minor pathway for direct adenosine incorporation. It may have a rather unusual substrate specificity because it is able to recognize adenosine, tubercidin, and formycin A as substrates, but not 9-deaza-adenosine or adenine arabinoside.
Mol Biochem Parasitol 1985 Aug
PMID:Action of tubercidin and other adenosine analogs on Schistosoma mansoni schistosomules. 392 87

From a mutagenized population of wildtype Leishmania donovani promastigotes, a clonal cell line, TUBA2, was isolated by virtue of its ability to survive and grow in 20 microM tubercidin (7-deazaadenosine). The TUBA2 clone was also 1000-fold less sensitive than the parental line to growth inhibition by formycin A, another cytotoxic adenosine analog. Parental and mutant cells, however, were equally sensitive to growth inhibition by formycin B, allopurinol riboside, and 6-thioguanosine. Mutant cell extracts, unlike those prepared from wildtype cells, did not phosphorylate radiolabelled adenosine, tubercidin, or formycin A. Intact adenosine kinase-deficient cells did not accumulate exogenous tubercidin or formycin A but incorporated [14C]adenosine at rates 25% of those found for parental cells. The uptake data suggest that adenosine kinase plays an important role in the metabolism of adenosine but indicate alternative metabolic pathways for this nucleoside. The metabolism of adenosine to the nucleotide level in TUBA2 cells appears to be initiated via deribosylation to adenine. Significant amounts of both adenosine hydrolytic and adenosine phosphorylytic activities have been detected in L. donovani promastigotes. Furthermore, L. donovani extracts could slowly catalyze the deamination of formycin A. The isolation and characterization of adenosine kinase-deficient cells has provided considerable insight into the function of the purine pathway in L. donovani.
Mol Biochem Parasitol 1984 Jun
PMID:Characterization of a mutant Leishmania donovani deficient in adenosine kinase activity. 609 Aug 96

The metabolism and inhibitory activity of 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin, RTC, NSC 286193) was studied in Chinese hamster ovary (CHO) cells and a series of mutants derived from them. Isotope incorporation experiments indicate dramatic inhibition of DNA and RNA synthesis by tiazofurin but little or no effect on protein synthesis. In CHO cells, tiazofurin is more toxic than ribavirin and also demonstrates a stronger inhibition of guanine nucleotide synthesis. Tiazofurin is phosphorylated by crude extracts of CHO cells. Variant cell lines lacking adenosine kinase (EC 2.7.1.20) or deoxycytidine kinase (EC 2.7.1.74) show no resistance to tiazofurin, suggesting that these enzymes are not responsible for the phosphorylation of tiazofurin. The inhibitory activity of this agent can be reversed by exogenously supplied guanine, suggesting that the inhibition is due, at least in part, to guanylate deficiency.
Mol Pharmacol 1983 Mar
PMID:Action of 2-beta-d-Ribofuranosylthiazole-4-carboxamide (tiazofurin) in Chinese hamster ovary and variant cell lines. 618 36

Plasmodium falciparum trophozoites were isolated by mechanical rupture of infected human erythrocytes followed by a series of differential centrifugation steps. After lysis with sonication, the 100 000 x g supernatant of parasites and uninfected host cells was used to determine the specific activities of a number of enzymes involved in purine and pyrimidine metabolism. P. falciparum possessed the purine salvage enzymes: adenosine deaminase, purine nucleoside phosphorylase, hypoxanthine-guanine phosphoribosyltransferase (PRTase), xanthine PRTase, adenine PRTase, adenosine kinase. The last two enzymes, however, were present at much lower activity levels. Hypoxanthine was converted (presumably via IMP) into adenine and guanine nucleotides only in the presence both of supernatant and membrane fractions of P. falciparum. Two enzymes involved in the de novo synthesis of pyrimidines, orotic acid PRTase, and orotidine 5'-phosphate decarboxylase, were present in parasite extracts as were the enzymes for pyrimidine nucleotide phosphorylation: UMP-CMP kinase, dTMP kinase, nucleoside diphosphate kinase. Xanthine oxidase, CTP synthetase, cytidine deaminase and several kinases for the salvage of pyrimidine nucleosides were not detected in the parasites. Both phosphoribosyl pyrophosphate synthetase and uracil PRTase were present but at low activity levels. Human erythrocytes displayed similar but not identical enzyme patterns. Enzyme specific activities, however, were generally much lower than those of the corresponding parasite enzymes.
Mol Biochem Parasitol 1982 May
PMID:Enzymes of purine and pyrimidine metabolism from the human malaria parasite, Plasmodium falciparum. 628 90

Ribonucleosides of some pyrazolo [3,4-d] pyrimidines have been shown to be potent anticoccidial agents. To investigate their interactions with adenosine kinase, this enzyme was purified by affinity chromatography from the sporulated oocysts of 3 avian coccidia, Eimeria tenella, E. acervulina and E. brunetti as well as from chicken liver. Comparative studies revealed several differences among the enzymes. Magnesium appeared not to be inhibitor of the E. tenella enzyme but did inhibit the enzymes from the other three sources. ATP in excess of the magnesium concentration strongly inhibited the E. brunetti enzyme but had only a small effect on the other enzymes. The chicken liver enzyme utilized a broader variety of triphosphate donors than did any of the enzymes from Eimeria species. ATP, dATP, GTP, dGTP and ITP was the best substrates. Studies with pyrazolo [3,4-d] pyrimidine nucleosides revealed two groups of enzymes with similar inhibitor specificities, the chicken liver and E. Acervulina vs. the E. tenella and E. brunetti enzyme. This grouping roughly correlates with the in vivo anticoccidial specificity of these compounds. Substrate specificity studies using two 4-substituted pyrazolo [3,4-d] pyrimidine ribonucleosides (ethylthio- and cinnamylthio-), which have shown potent anticoccidial activity in vivo, revealed that each served as a substrate for the enzymes from E. tenella and E. acervulina. The E. tenella enzyme was the more efficient at the phosphorylation of those compounds. However, only the ethylthio- compound was detectably phosphorylated by the enzyme from E. brunetti. In contrast to the inhibitor specificity, the substrate activities of these nucleosides do not correlate well with their in vivo anticoccidial activity.
Mol Biochem Parasitol 1982 Oct
PMID:Purification, characterization, substrate and inhibitor specificity of adenosine kinase from several Eimeria species. 629 13

Stable mutants which are approximately three- and eightfold resistant to the pyrazolopyrimidine nucleosides formycin A and formycin B (FomR) have been selected in a single step from mutagenized Chinese hamster ovary cells. In cell extracts, the two FomR mutants which were examined were both found to contain no measurable activity of the enzyme adenosine kinase (AK). However, cross-resistance studies with other adenosine analogs such as toyocamycin and tubercidin show that these mutants are distinct from toyocamycin or tubercidin resistant (Toyr) mutants which also contain no measurable AK activity in cell extracts. Studies on the uptake and incorporation of [3H]adenosine and [3H]tubercidin by various mutants and parental cell lines show that unlike the Toyr mutants, which are severely deficient in the phosphorylation of these compounds, the FomR mutants possess nearly normal capacity to phosphorylate these compounds and incorporate them into cellular macromolecules. These results suggest that the FomR mutants contain normal levels of AK activity in vivo. In cell hybrids formed between FomR X FomS cells and FomR X Toyr cells, the formycin-resistant phenotype of both of the FomR mutants behaved codominantly. However, the extracts from these hybrid cells contained either congruent to 50% (FomR X FomS) or no measurable (FomR X Toyr) AK activity, indicating that the lesion in these mutants neither suppresses the wild-type AK activity nor complements the AK deficiency of the Toyr mutants. The presence of AK activity in the FomR mutants in vivo, but not in their cell extracts, along with the codominant behavior of the mutants in hybrids, indicates that the lesions in the FomR mutant are of a novel nature. It is suggested that the genetic lesion in these mutants affects AK activity indirectly and that it may involve an essential cellular function which exists in a complex form with AK. Some implications of these results regarding the mechanism of action of formycin B are discussed.
Mol Cell Biol 1983 Aug
PMID:Formycin B-resistant mutants of Chinese hamster ovary cells: novel genetic and biochemical phenotype affecting adenosine kinase. 631 94

Some enzymes of purine salvage were detected in the cell-free preparations from bloodstream forms of African trypanosomes: Trypanosoma vivax; T. brucei and T. congolense. Extracts of trypanosomes cleave adenosine and inosine hydrolytically except in T. congolense where adenosine cleavage was mediated by a phosphorylase. All the trypanosomes apparently lacked adenosine deaminase. Adenine aminohydrolase was found only in T. vivax while adenosine monophosphate deaminase was detected in T. brucei and T. congolense. There was no detectable adenosine kinase activity in T. brucei. A pathway is proposed for the metabolism of purines in these trypanosomes.
Mol Biochem Parasitol 1983 Dec
PMID:Comparative aspects of purine metabolism in some African trypanosomes. 641 98

The anaerobic protozoon Tritrichomonas foetus was found incapable of de novo purine synthesis by its failure to incorporate radiolabeled glycine or formate into the nucleotide pool. It had, on the other hand, high activities in incorporating adenine, hypoxanthine or inosine. Radiolabel pulse-chase experiments indicated that adenine, hypoxanthine and inosine all entered the pool through conversion to IMP. The parasite contained hypoxanthine phosphoribosyl transferase, adenine deaminase and inosine phosphorylase, but no adenine phosphoribosyl transferase, inosine kinase or inosine phosphotransferase activity. Adenine and inosine had to be converted to hypoxanthine before incorporation. Adenosine was also rapidly converted to hypoxanthine in T. foetus cell-free extracts, but the presence of adenosine kinase in the parasite allowed some conversion of adenosine directly to AMP. Guanine and xanthine were directly incorporated into GMP and XMP, probably due to the guanine and xanthine phosphoribosyl transferase. There were also strong enzyme activities which convert guanosine to guanine and guanine to xanthine. A guanosine phosphotransferase was found in the 10(5) X g sedimentable fraction of T. foetus, and was capable of converting some guanosine to GMP. This network of T. foetus purine salvage suggests the importance of hypoxanthine-guanine-xanthine phosphoribosyl transferase activities in the parasite.
Mol Biochem Parasitol 1983 Aug
PMID:Purine salvage by Tritrichomonas foetus. 663 66

Hyperthyroidism induces a number of metabolic and physiological changes in the heart including hypertrophy, increase in inotropic status, and alterations of myocardial energy metabolism. The effects of hyperthyroidism on adenosine metabolism which is intimately involved in the control of many aspects of myocardial energetics, have not been clarified. The aim of this study was thus to evaluate the potential role of adenosine in the altered physiology of the hyperthyroid heart. Transport of adenosine was studied in cardiomyocytes isolated from hyperthyroid and euthyroid rats. Activities of different enzymes of purine metabolism were studied in heart homogenates and concentrations of nucleotide and creatine metabolites were determined in hearts freeze-clamped in situ. Both transport of adenosine into cardiomyocytes and the rate of intracellular phosphorylation were higher in the hyperthyroid rat. At 10 microM concentration, adenosine transport rates were 275 and 197 pmol/min/mg protein in hyperthyroid and euthyroid cardiomyocytes respectively whilst rates of adenosine phosphorylation were 250 and 180 pmol/min/mg prot. An even more pronounced difference was observed if values were expressed per number of cells due to cardiomyocyte enlargement. Hyperthyroidism was associated with a 20% increase in adenosine kinase, 30% decrease in membrane 5'-nucleotidase and 15% decrease in adenosine deaminase activities measured in heart homogenates. In addition there was a substantial depletion in the total creatine pool from 63.7 to 41.6 mumol/g dry wt, a small decrease in the adenylate pool (from 27.2 to 24.3 mumol/g dry wt) and an elevation of the guanylate pool (from 1.22 to 1.36). These results show that adenosine transport and phosphorylation capacity is enhanced in hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1995 Feb 23
PMID:Hyperthyroidism increases adenosine transport and metabolism in the rat heart. 759 49

Nucleoside transport may play a critical role in successful intracellular parasitism by Toxoplasma gondii. This protozoan is incapable of de novo purine synthesis, and must salvage purines from the host cell. We characterized purine transport by extracellular T. gondii tachyzoites, focusing on adenosine, the preferred salvage substrate. Although wild-type RH tachyzoites concentrated [3H]adenosine 1.8-fold within 30 s, approx. half of the [3H]adenosine was converted to nucleotide, consistent with the known high parasite adenosine kinase activity. Studies using an adenosine kinase deficient mutant confirmed that adenosine transport was non-concentrative. [14C]Inosine, [14C]hypoxanthine and [3H]adenine transport was also rapid and non-concentrative. Adenosine transport was inhibited by dipyridamole (IC50 approx. 0.7 microM), but not nitrobenzylthioinosine (15 microM). Transport of inosine, hypoxanthine and adenine was minimally inhibited by 10 microM dipyridamole, however. Competition experiments using unlabeled nucleosides and bases demonstrated distinct inhibitor profiles for [3H]adenosine and [14C]inosine transport. These results are most consistent with a single, dipyridamole-sensitive, adenosine transporter located in the T. gondii plasma membrane. Additional permeation pathways for inosine, hypoxanthine, adenine and other purines may also be present.
Mol Biochem Parasitol 1995 Mar
PMID:Toxoplasma gondii tachyzoites possess an unusual plasma membrane adenosine transporter. 763 15


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