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pharmacology
substrate 6-mercaptopurine-2'-deoxyriboside is of special interest, because, in contrast to a nucleoside, its parent purine is highly cytotoxic and is known as one of the first compounds applied as anti-cancer drugs
analysis
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determination of enzymic activity using commercially available substrate 2-amino-6-mercapto-7-methylpurine ribonucleoside and photometric assessment of the reaction
analysis
development of a set of empirical scoring functions and its application to evaluate binding affinities and docking results
analysis
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electrochemical biosensor to assay purine nucleoside phosphorylase activity based on the facilitation of sliver nanoparticles, which are modified on an electrode surface, to the electron transfer reactivity of guanosine and guanine. Assay displays a broad linear range of 4-20 units/ml with a detection limit of 0.1 unit/ml. Additional development development of a rapid UVvis spectroscopy assay method for PNP activity
drug development
the enzyme is a target for drug development
drug development
differences in specificity between homotrimeric (including human enzyme) and homohexameric PNPs, including various pathogenic organisms, make them interesting potential drug targets
drug development
differences in specificity between homotrimeric (including human enzyme) and homohexameric PNPs, including various pathogenic organisms, make them interesting potential drug targets
drug development
differences in specificity between homotrimeric (including human enzyme) and homohexameric PNPs, including various pathogenic organisms, make them interesting potential drug targets
drug development
owing to their key role in the purine salvage pathway, PNPs are attractive targets for drug design against some pathogens
drug development
Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo
drug development
the enzyme is a target for development of anti-malarial drugs
medicine
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medicine
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the purine nucleoside phosphorylases may play a role in chemotherapy in two ways: 1. by catalyzing the breakdown of nucleosides that contain purine analogs and by promoting the incorporation of purine and pyrimidine analogs into the nucleotides and nucleic acids of the cell by increasing the intracellular pool of ribose 1-phosphate and deoxyribose 1-phosphate
medicine
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the enzyme constitutes a target for antitrichomonial chemotherapy
medicine
overview of clinical aspects
medicine
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since PNP inhibitors block the catabolism of purine nucleosides to hypoxanthine and guanine, precursors of uric acid, they should be useful in the treatment of goat and other hyperuricemic conditions. A number of parasites, including the malaria parasite, lacking the ability to synthesize purine nucleotides de novo, must utilize host purines, formed by PBP, for DNA synthesis. Thus inhibition of PNP could prevent the spread of parasitic infection
medicine
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structural data from crystal structure may be useful in designing prodrugs that can be activated by E. coli enzyme but not the human enzyme
medicine
high-resolution structure may serve for design of inhibitors with potential pharmacological application
medicine
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the enzyme inhibitors 8-amino-5'-deoxy-5'-chloroguanosine and 8-amino-9-benzylguanine may have some antimalarial potential by limiting hypoxanthine production in the parasite-infected erythrocyte
medicine
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delivery of replication-competent retrovirus expressing Escherichia coli purine nucleoside phosphorylase increases the metabolism of the prodrug, fludarabine phosphate and suppresses the growth of bladder tumor xenografts. Replication-competent retroviral vectors are a potentially efficient gene delivery method and replication-competent retroviral vector mediated PNP gene transfer and fludarabine phosphate treatment might be a novel and potentially therapeutic modality for bladder cancer
medicine
trans-activator of transcription-mediated long-term intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice
medicine
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endogenous PNP deficiency leads to specific T-cell immunodeficiency, a genetic disease. PNP inhibition leads to the elevation of 2'-deoxyguanosine levels and accumulation of intracellular deoxyguanosine 5'-triphosphate, inducing cellular apoptosis. Forodesine is a highly potent, orally active, rationally designed PNP inhibitor that is active in preclinical studies with malignant cells and clinical utility against T-cell acute lymphoblastic leukemia and cutaneous T-cell lymphoma
medicine
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purine nucleoside phosphorylase inhibition is a novel therapeutic approach for B-cell lymphoid malignancies
medicine
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construction of lentiviral vectors containing the human purine-nucleoside phosphorylase gene and transduction of lymphocytes from a purine nucelotide phosphorylase-deficient patient as well as lymphocytes, fibroblasts and bone marrow from purine nucelotide phosphorylase-deficient mice. Transduction significantly increases purine nucelotide phosphorylase expression in purine nucelotide phosphorylase-deficient human lymphocytes, murine lymphocytes, fibroblasts and bone marrow cells. Lenti-purine nucelotide phosphorylase transduction also significantly improves the proliferation of PNP-/- murine lymphocyte and survival of irradiated purine nucelotide phosphorylase-/- fibroblasts. Transduced purine nucelotide phosphorylase-/- bone marrow cells transplanted into purine nucelotide phosphorylase-/- mice express purine nucelotide phosphorylase in vivo, partially restore urinary uric acid secretion, show improved thymocytes maturation, increased weight gain and extended survival of the mice. 12 weeks after transplant, the benefit of lenti-purine nucelotide phosphorylase transduced cells and normal bone marrow diminishes and the percentage of engrafted donor cells decrease
medicine
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expression of the Escherichia coli purine nucleoside phosphorylase/9-(2-deoxy-beta-dribofuranosyl)-6-methylpurine suicide gene system in human hepatocarcinoma cells together with a chimeric human alpha-fetoprotein promoter. In the presence of hypoxia, the Escherichia coli purine nucleoside phosphorylase gene directed by the human promoter is specifically expressed in two human hepatocarcinoma cell lines and, the therapy yields significant and selective cytotoxicity in both alpha-fetoprotein-positive and low-alpha-fetoprotein-generating hepatocarcinoma cells
medicine
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mutation A117 leads to purine-nucleoside phosphorylase deficiency. Mutation occured in two sisters with a fatal course due to delay in diagnosis. The first patient developed a liver abscess by Aspergillus fumigatus and the second patient developed Mycobacterium tuberculosis complex lymphadenitis and probable pulmonary tuberculosis due to disseminated BCG infection. The patients also suffered from sclerosing cholangitis
medicine
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use of mutant E201Q/N243D in Antibody Dependent Enzyme Prodrug Therapy ADEPT by fusion to the human anti-HER2/neu single chain Fv. In vitro the construct binds specifically to HER2/neu expressing tumor cells and localizes the enzyme to tumor cells, where the enzymatic activity of the mutant, but not the wild type enzyme, results in phosphorolysis of the prodrug, 2-fluoro-2'-deoxyadenosine to the cytotoxic drug 2-fluoroadenine causing inhibition of tumor cell proliferation
medicine
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for inhibitor (S)-3-(guanin-9-yl)pyrrolidin-N-ylcarbonylphosphonic acid, Ki values widely vary from 16 to 100 nM for enzyme from cancer cell lines. For inhibitor (3S,4R)-4-(guanin-9-yl)-3-hydroxypyrrolidin-1-N-ylcarbonylphosphonic acid, Ki values are around 10 to 24 nM for enzyme from cancer cell lines
synthesis
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efficient overexpression of thermostable enzyme in Escherichia coli. The increase of the cultivation temperature from 30°C to 42°C allows a more than 10fold increase of activity per cell and optimizing the 5 mRNA gene sequence further increases the activity per cell 1.7fold at 42°C
synthesis
synthesis of ribavirin by the enzyme and comparison with Escherichia coli enzyme. A cold-adapted Pseudoalteromonas enzyme shows approximately 15 degrees lower optimum temperature and 1.80fold higher catalytic efficiency at 37°C within substrate inosine than its homolog from Escherichia coli
synthesis
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two-step efficient synthesis of 5-methyluridine, a intermediate in the synthesis of anti-AIDS drug such as stavudine and zidovudine
synthesis
use of agar from four different polymer carriers as a suitable matrix for whole recombinant cell entrapment. Although the immobilization process reduces the substrate affinity and catalytic efficiency of recombinant cells, it can significantly enhance the stability and reusability of these cells. The immobilized whole cell biocatalyst is applied to produce ribavirin, as a model nucleoside synthesis reaction showing relative high productivity of rabavirin and quick reaction time
synthesis
the enzyme is a valuable industrial biocatalysts for high-temperature reactions that produce nucleoside drugs in high yields
synthesis
enzymatic ribosylation of fluorescent 8-azapurine derivatives, like 8-azaguanine and 2,6-diamino-8-azapurine, with purine-nucleoside phosphorylase (PNP) as a catalyst, leads to N9, N8, and N7-ribosides. The final proportion of the products may be modulated by point mutations in the enzyme active site. As an example, ribosylation of the latter substrate by wild-type calf PNP gives N7- and N8-ribosides, while the N243D mutant directs the ribosyl substitution at N9- and N7-positions. The same mutant allows synthesis of the fluorescent N7-D-ribosyl-8-azaguanine. The mutated form of the Escherichia coli PNP, D204N, can be utilized to obtain non-typical ribosides of 8-azaadenine and 2,6-diamino-8-azapurine as well. The N7- and N8-ribosides of the 8-azapurines can be analytically useful, as illustrated by N7-D-ribosyl-2,6-diamino-8-azapurine, which is a good fluorogenic substrate for mammalian forms of PNP, including human blood PNP, while the N8-riboside is selective to the Escherichia coli enzyme
synthesis
enzymatic ribosylation of fluorescent 8-azapurine derivatives, like 8-azaguanine and 2,6-diamino-8-azapurine, with purine-nucleoside phosphorylase (PNP) as a catalyst, leads to N9, N8, and N7-ribosides. The final proportion of the products may be modulated by point mutations in the enzyme active site. As an example, ribosylation of the latter substrate by wild-type calf PNP gives N7- and N8-ribosides, while the N243D mutant directs the ribosyl substitution at N9- and N7-positions. The same mutant allows synthesis of the fluorescent N7-D-ribosyl-8-azaguanine. The N7- and N8-ribosides of the 8-azapurines can be analytically useful, as illustrated by N7-D-ribosyl-2,6-diamino-8-azapurine, which is a good fluorogenic substrate for mammalian forms of PNP, while the N8-riboside is selective to the Escherichia coli enzyme
synthesis
enzyme AmPNP is an excellent biocatalyst for the industrial production of purine nucleoside analogues, biosynthesis of purine nucleoside analogues, overview
synthesis
enzyme is useful in biocatalytic production of 2,6-diaminopurine 2'-deoxyriboside
synthesis
enzyme is useful in biocatalytic production of 2,6-diaminopurine riboside and 5-methyluridine
synthesis
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enzyme is useful in biocatalytic production of 2,6-diaminopurine riboside, 2,6-dichloropurine riboside, 6-chloro-2-fluoropurine riboside, 2-chloroadenine riboside, 2-fluoroadenine riboside, 2,6-diaminopurine 2'-deoxyriboside, 2,6-dichloropurine 2'-deoxyriboside, 6-chloro-2-fluoropurine 2'-deoxyriboside, 2-chloro-2'-deoxyadenosine (cladribine), and 2-fluoro-2'-deoxyadenosine, as well as of 2,6-diaminopurine arabinoside, 2,6-dichloropurine arabinoside, and 6-chloro-2-fluoropurine arabinoside
synthesis
enzyme is useful in biocatalytic production of 2-chloro-2'-deoxyadenosine (Cladribine), and 2-fluoroadenine arabinoside
synthesis
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enzyme is useful in biocatalytic production of 2-fluoro-2'-deoxyadenosine and 2'-deoxy-2'-fluoroadenosine
synthesis
enzyme is useful in biocatalytic production of 5-methyluridine
synthesis
important application of PNP is in chemo-enzymatic synthesis of bioactive nucleoside analogues, utilizing various types of PNP among others. This application may be extended to tricyclic nucleobase analogues, particularly to adenine, isoguanine, and guanine derivatives. In particular, N9-D-riboside of can be obtained quantitatively from 1,N2-ethenoguanine, and N9-beta-D- and N7-beta-D-ribosides of 1,N6-etheno-isoguanine as a mixture, using the Escherichia coli PNP as a biocatalyst
synthesis
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the enzyme is a valuable industrial biocatalysts for high-temperature reactions that produce nucleoside drugs in high yields
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synthesis
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enzyme is useful in biocatalytic production of 2,6-diaminopurine 2'-deoxyriboside
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synthesis
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synthesis of ribavirin by the enzyme and comparison with Escherichia coli enzyme. A cold-adapted Pseudoalteromonas enzyme shows approximately 15 degrees lower optimum temperature and 1.80fold higher catalytic efficiency at 37°C within substrate inosine than its homolog from Escherichia coli
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synthesis
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enzyme is useful in biocatalytic production of 2-fluoro-2'-deoxyadenosine and 2'-deoxy-2'-fluoroadenosine
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synthesis
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enzyme is useful in biocatalytic production of 2-fluoro-2'-deoxyadenosine and 2'-deoxy-2'-fluoroadenosine
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synthesis
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enzyme is useful in biocatalytic production of 2,6-diaminopurine riboside, 2,6-dichloropurine riboside, 6-chloro-2-fluoropurine riboside, 2-chloroadenine riboside, 2-fluoroadenine riboside, 2,6-diaminopurine 2'-deoxyriboside, 2,6-dichloropurine 2'-deoxyriboside, 6-chloro-2-fluoropurine 2'-deoxyriboside, 2-chloro-2'-deoxyadenosine (cladribine), and 2-fluoro-2'-deoxyadenosine, as well as of 2,6-diaminopurine arabinoside, 2,6-dichloropurine arabinoside, and 6-chloro-2-fluoropurine arabinoside
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synthesis
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enzyme is useful in biocatalytic production of 2,6-diaminopurine 2'-deoxyriboside
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synthesis
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enzyme AmPNP is an excellent biocatalyst for the industrial production of purine nucleoside analogues, biosynthesis of purine nucleoside analogues, overview
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