Substrate Spectra of Nucleoside Phosphorylases and their Potential in the Production of Pharmaceutically Active Compounds

Yehia, Heba; Kamel, Sarah; Paulick, Katharina; Wagner, Anke; Neubauer, Peter

doi:10.2174/1381612823666171024155811

Cited by 34 publications

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“…NPases catalyze the phosphorolysis of nucleosides to pentose‐1‐phosphates, as well as the corresponding reverse reaction (Scheme ). They are generally classified as either pyrimidine nucleoside phosphorylases (Py‐NPases) or purine nucleoside phosphorylases (Pu‐NPases), depending on their substrate spectra …”

Section: Introductionmentioning

confidence: 99%

Thermodynamic Reaction Control of Nucleoside Phosphorolysis

et al. 2020

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Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose‐1‐phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase‐catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate‐specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature‐dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis.

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Section: Introductionmentioning

confidence: 99%

Thermodynamic Reaction Control of Nucleoside Phosphorolysis

et al. 2020

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“…Numerous reviews on nucleoside phosphorylases are available. The structural organization of these enzymes [1,2], the substrate specificity and methods for the synthesis of valuable nucleosides [3][4][5][6], and metabolism in biological systems [7][8][9][10] have been considered.…”

Section: Nucleoside Phosphorylases As Key Enzymes In Nucleoside Metabmentioning

confidence: 99%

Strained Conformations of Nucleosides in Active Sites of Nucleoside Phosphorylases

2020

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Nucleoside phosphorylases catalyze the reversible phosphorolysis of nucleosides to heterocyclic bases, giving α-d-ribose-1-phosphate or α-d-2-deoxyribose-1-phosphate. These enzymes are involved in salvage pathways of nucleoside biosynthesis. The level of these enzymes is often elevated in tumors, which can be used as a marker for cancer diagnosis. This review presents the analysis of conformations of nucleosides and their analogues in complexes with nucleoside phosphorylases of the first (NP-1) family, which includes hexameric and trimeric purine nucleoside phosphorylases (EC 2.4.2.1), hexameric and trimeric 5′-deoxy-5′-methylthioadenosine phosphorylases (EC 2.4.2.28), and uridine phosphorylases (EC 2.4.2.3). Nucleosides adopt similar conformations in complexes, with these conformations being significantly different from those of free nucleosides. In complexes, pentofuranose rings of all nucleosides are at the W region of the pseudorotation cycle that corresponds to the energy barrier to the N↔S interconversion. In most of the complexes, the orientation of the bases with respect to the ribose is in the high-syn region in the immediate vicinity of the barrier to syn ↔ anti transitions. Such conformations of nucleosides in complexes are unfavorable when compared to free nucleosides and they are stabilized by interactions with the enzyme. The sulfate (or phosphate) ion in the active site of the complexes influences the conformation of the furanose ring. The binding of nucleosides in strained conformations is a characteristic feature of the enzyme–substrate complex formation for this enzyme group.

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“…PNP is responsible for the regulation of the nucleoside concentrations within the living cells, and it is a target of various types of pharmaceutical interventions [12,13], including gene therapy of some inherited immunological deficiencies [14] and gene therapy of solid tumors [15]. Additionally, PNP's from various sources are utilized as biocatalysts in chemo-enzymatic syntheses of various nucleoside analogs of pharmaceutical and/or analytical significance [16][17][18][19][20]. Our previous investigations have shown that PNP isolated from E. coli, which is known to possess a broad specificity toward various base and nucleoside analogs [16], is also active toward many tri-cyclic nitrogen bases, derived from adenine and guanine [17,21,22], producing in the phosphate free media many potentially useful ribosides, using β-d-ribose-1-phosphate (R1P) as a ribose source.…”

Section: Introductionmentioning

confidence: 99%

Tricyclic Nucleobase Analogs and Their Ribosides as Substrates and Inhibitors of Purine-Nucleoside Phosphorylases III. Aminopurine Derivatives

Stachelska-Wierzchowska

Wierzchowski

Górka

et al. 2020

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Etheno-derivatives of 2-aminopurine, 2-aminopurine riboside, and 7-deazaadenosine (tubercidine) were prepared and purified using standard methods. 2-Aminopurine reacted with aqueous chloroacetaldehyde to give two products, both exhibiting substrate activity towards bacterial (E. coli) purine-nucleoside phosphorylase (PNP) in the reverse (synthetic) pathway. The major product of the chemical synthesis, identified as 1,N2-etheno-2-aminopurine, reacted slowly, while the second, minor, but highly fluorescent product, reacted rapidly. NMR analysis allowed identification of the minor product as N2,3-etheno-2-aminopurine, and its ribosylation product as N2,3-etheno-2-aminopurine-N2-β-d-riboside. Ribosylation of 1,N2-etheno-2-aminopurine led to analogous N2-β-d-riboside of this base. Both enzymatically produced ribosides were readily phosphorolysed by bacterial PNP to the respective bases. The reaction of 2-aminopurine-N9-β -d-riboside with chloroacetaldehyde gave one major product, clearly distinct from that obtained from the enzymatic synthesis, which was not a substrate for PNP. A tri-cyclic 7-deazaadenosine (tubercidine) derivative was prepared in an analogous way and shown to be an effective inhibitor of the E. coli, but not of the mammalian enzyme. Fluorescent complexes of amino-purine analogs with E. coli PNP were observed.

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Substrate Spectra of Nucleoside Phosphorylases and their Potential in the Production of Pharmaceutically Active Compounds

Cited by 34 publications

References 0 publications

Thermodynamic Reaction Control of Nucleoside Phosphorolysis

Thermodynamic Reaction Control of Nucleoside Phosphorolysis

Strained Conformations of Nucleosides in Active Sites of Nucleoside Phosphorylases

Tricyclic Nucleobase Analogs and Their Ribosides as Substrates and Inhibitors of Purine-Nucleoside Phosphorylases III. Aminopurine Derivatives

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