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David K Stammers - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for non Competitive Product inhibition in human thymidine phosphorylase implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Jan Balzarini, Mariajesus Perezperez, David K Stammers
    Abstract:

    HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

  • Structural basis for non-Competitive Product inhibition in human thymidine phosphorylase: implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Maris-jésus Pérez-pérez, Jan Balzarini, David K Stammers
    Abstract:

    Human Thymidine Phosphorylase (HTP), also known as Platelet-derived endothelial cell growth factor (PD-ECGF) or Gliostatin has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis, therefore is a prime target for drug design including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose-phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears able to reassociate with HTP after its initial ordered release before ribose-phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase (PYNP) and it defines a sub site that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active site cleft and appears to stabilise the dimer interface and the closed conformation by hydrogen bonding. This work will assist in the design of HTP inhibitors which could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

Annelies Bronckaers - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for non Competitive Product inhibition in human thymidine phosphorylase implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Jan Balzarini, Mariajesus Perezperez, David K Stammers
    Abstract:

    HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

  • Structural basis for non-Competitive Product inhibition in human thymidine phosphorylase: implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Maris-jésus Pérez-pérez, Jan Balzarini, David K Stammers
    Abstract:

    Human Thymidine Phosphorylase (HTP), also known as Platelet-derived endothelial cell growth factor (PD-ECGF) or Gliostatin has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis, therefore is a prime target for drug design including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose-phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears able to reassociate with HTP after its initial ordered release before ribose-phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase (PYNP) and it defines a sub site that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active site cleft and appears to stabilise the dimer interface and the closed conformation by hydrogen bonding. This work will assist in the design of HTP inhibitors which could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

Sandra Liekens - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for non Competitive Product inhibition in human thymidine phosphorylase implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Jan Balzarini, Mariajesus Perezperez, David K Stammers
    Abstract:

    HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

  • Structural basis for non-Competitive Product inhibition in human thymidine phosphorylase: implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Maris-jésus Pérez-pérez, Jan Balzarini, David K Stammers
    Abstract:

    Human Thymidine Phosphorylase (HTP), also known as Platelet-derived endothelial cell growth factor (PD-ECGF) or Gliostatin has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis, therefore is a prime target for drug design including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose-phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears able to reassociate with HTP after its initial ordered release before ribose-phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase (PYNP) and it defines a sub site that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active site cleft and appears to stabilise the dimer interface and the closed conformation by hydrogen bonding. This work will assist in the design of HTP inhibitors which could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

Jan Balzarini - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for non Competitive Product inhibition in human thymidine phosphorylase implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Jan Balzarini, Mariajesus Perezperez, David K Stammers
    Abstract:

    HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end com-plex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406–415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

  • Structural basis for non-Competitive Product inhibition in human thymidine phosphorylase: implications for drug design
    Biochemical Journal, 2006
    Co-Authors: Kamel El Omari, Annelies Bronckaers, Sandra Liekens, Maris-jésus Pérez-pérez, Jan Balzarini, David K Stammers
    Abstract:

    Human Thymidine Phosphorylase (HTP), also known as Platelet-derived endothelial cell growth factor (PD-ECGF) or Gliostatin has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis, therefore is a prime target for drug design including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose-phosphate and Product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears able to reassociate with HTP after its initial ordered release before ribose-phosphate and induces the closed conformation, hence explaining the mechanism of non-Competitive Product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase (PYNP) and it defines a sub site that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active site cleft and appears to stabilise the dimer interface and the closed conformation by hydrogen bonding. This work will assist in the design of HTP inhibitors which could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

Ibrahim M. Abu-reesh - One of the best experts on this subject based on the ideXlab platform.

  • Optimal design of continuously stirred membrane reactors in series using Michaelis-Menten kinetics with Competitive Product inhibition: theoretical analysis
    Desalination, 2005
    Co-Authors: Ibrahim M. Abu-reesh
    Abstract:

    Analytical expressions were derived for the optimal design (based on the minimum of the volume of the total number of reactors) of N continuously stirred membrane reactors (CSMRs) performing the enzyme-catalyzed reaction described by Michaelis-Menten kinetics with Competitive Product inhibition. The influence of membrane selectivity for both substrate and Product on the total dimensionless residence time of the reactors (overall volume) was determined. The optimal design of N CSMRs (variable volume reactors) was compared with equal volume membrane reactors required to achieve the same degree of substrate conversion. The effect of kinetic and operating parameters on the performance of membrane reactors was determined. Optimization results show that membrane reactors are superior to continuously stirred tank reactors (CSTRs) in series at a high substrate rejection coefficient and low Product rejection coefficient, high substrate conversion and using a small number of reactors. Also a high dimensionless Michaelis-Menten constant, high dimensionless inhibition constant and low substrate concentration in the feed to the first reactor improved the performance of the membrane reactors vs. CSTRs in series. The reduction in total volume of the optimal membrane reactors compared to CSTRs in series was up to 86% for the conditions in this work. A comparison between the optimum and equal volume design of membrane reactors in series showed no major difference in total volume between the two design criteria at a practical range of operating conditions. A volume reduction up to 16% was observed for the conditions in this work.