Purine nucleoside phosphorylases: properties, functions, and clinical aspects

Bzowska, Agnieszka; Kulikowska, Ewa; Shugar, David

doi:10.1016/s0163-7258(00)00097-8

Cited by 457 publications

(528 citation statements)

References 340 publications

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“…For example, complex nucleosides exhibit antibacterial activity by specific inhibition of cell-wall peptidoglycan biosynthesis (Kimura & Bugg, 2003), certain bacterial enzymes, such as purine nucleoside phosphorylases (Bzowska et al, 2000), and DNA ligases (Mills et al, 2011). In particular, adenosine analogues such as cordycepin (Ahn et al, 2000), 29-amino-29-deoxyadenosine and oxetanocin (Shimada et al, 1986), formycins (Bzowska et al, 2000), toyocamycin and its derivatives (Kimura & Bugg, 2003) and some purine derivatives (Tunçbilek et al, 2009) showed biological activity including antibiotic properties. More detailed investigations on the antimicrobial activity of various classes of still untested nucleoside derivatives need to be conducted in order to maximize the potential for developing nucleoside analogues for the treatment of bacterial infections.…”

Section: Introductionmentioning

confidence: 99%

In vitro antibacterial activity of different adenosine analogues

Vitali

Petrelli

Lambertucci

et al. 2012

Journal of Medical Microbiology

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Nucleoside analogues may represent good candidates for the discovery of new antibacterial agents, therefore, a library of adenosine analogues was assessed for their antibacterial activity, and the relationship between the structure and activity of these molecules was outlined. Antibacterial activity was evaluated against that of reference strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Escherichia coli and Pseudomonas aeruginosa. We tested 54 adenosine analogues, modified both at ribose and base moieties, including adenine and 1/3-deazaadenine derivatives substituted in the 2-and/or N 6 -positions and bearing N-9 sugar moieties, such as ribose, 29-deoxyribose, 39-deoxyribose, 29,39-dideoxyribose or cycloalkyl groups like cyclopentane. The data obtained, MIC and minimal bactericidal concentrations demonstrated that the presence of bulky substituents such as cycloheptyl and cyclooctyl rings on the N 6 -amino, together with a chlorine atom in the 2-position, conferred antibacterial activity against the Gram-positive group with MIC values ranging from 16 to 128 mg l "1 . The intact sugar moiety seemed to be not essential for antimicrobial activity and nucleosides bearing deoxyribose or cyclopentyl groups associated with bulky substituents in N 6 -position showed good antimicrobial properties. Furthermore, N-1 proved to be non-crucial and the 2-chloro-N 6 -cyclooctyl-1-deaza-39-deoxyadenosine and 29,39-dideoxyadenosine compounds were among the more active in the series with an MIC of 32 mg l "1 against Staph. aureus and Strep. pneumoniae. None of the analogues was active against the two Gram-negative species tested. Hence, adenosine derivatives bearing bulky substituents in the N 6 -position may represent good lead compounds for the future discovery of a novel series of antibacterial agents.

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Section: Introductionmentioning

confidence: 99%

In vitro antibacterial activity of different adenosine analogues

Vitali

Petrelli

Lambertucci

et al. 2012

Journal of Medical Microbiology

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“…2.4.2.1) catalyzes the reversible phosphorolytic cleavage of inosine, guanosine, and their 2 0 -deoxy forms to the corresponding bases and ribose-1-phosphate or 2 0 -deoxyribose-1-phosphate respectively ( Fig. 1) [4]. It is abundant in most mammalian cells.…”

Section: Purine Catabolismmentioning

confidence: 99%

“…It is abundant in most mammalian cells. Children with a specific deficiency in PNP have apparently normal B lymphocytic functions and competent humoral immunity, but lack T lymphocytic activity and cellular immunity [3,4].…”

Section: Purine Catabolismmentioning

confidence: 99%

From purines to basic biochemical concepts

Marini¹,

Ipata²

2007

Biochem Molecular Bio Educ

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Many high school biology courses address mainly the molecular and cellular basis of life. The complexity that underlies the most essential processes is often difficult for the students to understand; possibly, in part, because of the inability to see and explore them. Six simple practical experiments on purine catabolism as a part of a biochemistry course for 16-18 years students that require only simple equipment for thin layer chromatography have been developed, tried, and tested. These include detection and measurement of enzyme activities in biological extracts, detection of reversible and irreversible reactions, creating a pathway from consecutive reactions. They focus on purines because of their multifunctionality in biochemical processes. They allow students to grasp specific concepts and to use them as a framework for approaching metabolic complexity.

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“…1 More recently, the PNP enzyme has also been investigated as a potential target for the treatment of parasitic infectious diseases, such as malaria and schistosomiasis. [2][3][4] In particular, the parasite Schistosoma mansoni, one of the etiologic agents of human schistosomiasis, lacks the de novo pathway for purine biosynthesis and depends entirely on the salvage pathway for its purine requirements for synthesis of RNA and DNA. [5][6][7][8][9] In this context, the use of selective PNP inhibitors from S. mansoni (SmPNP) can cause purine starvation, leading to death of the parasite.…”

Section: Introductionmentioning

confidence: 99%

Descriptor-and fragment-based QSAR models for a series of Schistosoma mansoni purine nucleoside inhibitors

Freitas¹,

Postigo²,

Andricopulo³

et al. 2011

J. Braz. Chem. Soc.

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A enzima purina nucleosídeo fosforilase de Schistosoma mansoni (SmPNP) é um alvo molecular atrativo para o tratamento de importantes doenças infecciosas parasitárias, com especial ênfase para o seu papel na descoberta de novos fármacos contra a esquistossomose, uma doença tropical que afeta cerca de 200 milhões de pessoas em 74 áreas endêmicas no mundo todo. No presente trabalho, a potência inibitória foi determinada e estudos das relações quantitativas entre a estrutura e atividade (QSAR), baseados em descritores e fragmentos, foram desenvolvidos para uma série de 9-deazaguaninas que atuam como inibidores da SmPNP. Parâmetros estatísticos significantes (modelo baseado em descritor: r 2 = 0,79; q 2 = 0,62, r 2 pred = 0,52; e modelo baseado em fragmento: r 2 = 0,95; q 2 = 0,81; r 2 pred = 0,80) foram obtidos, indicando o potencial dos modelos para compostos ainda não testados. O modelo baseado em fragmento foi então usado para predizer a potência inibitória de um conjunto teste de compostos, e os valores preditos estão em boa concordância com os resultados experimentais.The enzyme purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive molecular target for the treatment of major parasitic infectious diseases, with special emphasis on its role in the discovery of new drugs against schistosomiasis, a tropical disease that affects millions of people worldwide. In the present work, we have determined the inhibitory potency and developed descriptor-and fragment-based quantitative structure-activity relationships (QSAR) for a series of 9-deazaguanine analogs as inhibitors of SmPNP. Significant statistical parameters (descriptor-based model: r 2 = 0.79, q 2 = 0.62, r 2 pred = 0.52; and fragment-based model: r 2 = 0.95, q 2 = 0.81, r 2 pred = 0.80) were obtained, indicating the potential of the models for untested compounds. The fragment-based model was then used to predict the inhibitory potency of a test set of compounds, and the predicted values are in good agreement with the experimental results.

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Purine nucleoside phosphorylases: properties, functions, and clinical aspects

Cited by 457 publications

References 340 publications

In vitro antibacterial activity of different adenosine analogues

In vitro antibacterial activity of different adenosine analogues

From purines to basic biochemical concepts

Descriptor-and fragment-based QSAR models for a series of Schistosoma mansoni purine nucleoside inhibitors

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