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Andrea T Hadfield - One of the best experts on this subject based on the ideXlab platform.

  • structure of insoluble rat sperm Glyceraldehyde 3 phosphate Dehydrogenase gapdh via heterotetramer formation with escherichia coli gapdh reveals target for contraceptive design
    Journal of Biological Chemistry, 2009
    Co-Authors: Jan Frayne, Abby Taylor, Gus Cameron, Andrea T Hadfield
    Abstract:

    Sperm Glyceraldehyde-3-Phosphate Dehydrogenase has been shown to be a successful target for a non-hormonal contraceptive approach, but the agents tested to date have had unacceptable side effects. Obtaining the structure of the sperm-specific isoform to allow rational inhibitor design has therefore been a goal for a number of years but has proved intractable because of the insoluble nature of both native and recombinant protein. We have obtained soluble recombinant sperm Glyceraldehyde-3-Phosphate Dehydrogenase as a heterotetramer with the Escherichia coli Glyceraldehyde-3-Phosphate Dehydrogenase in a ratio of 1:3 and have solved the structure of the heterotetramer which we believe represents a novel strategy for structure determination of an insoluble protein. A structure was also obtained where Glyceraldehyde 3-Phosphate binds in the Ps pocket in the active site of the sperm enzyme subunit in the presence of NAD. Modeling and comparison of the structures of human somatic and sperm-specific Glyceraldehyde-3-Phosphate Dehydrogenase revealed few differences at the active site and hence rebut the long presumed structural specificity of 3-chlorolactaldehyde for the sperm isoform. The contraceptive activity of α-chlorohydrin and its apparent specificity for the sperm isoform in vivo are likely to be due to differences in metabolism to 3-chlorolactaldehyde in spermatozoa and somatic cells. However, further detailed analysis of the sperm Glyceraldehyde-3-Phosphate Dehydrogenase structure revealed sites in the enzyme that do show significant difference compared with published somatic Glyceraldehyde-3-Phosphate Dehydrogenase structures that could be exploited by structure-based drug design to identify leads for novel male contraceptives.

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

  • structure of insoluble rat sperm Glyceraldehyde 3 phosphate Dehydrogenase gapdh via heterotetramer formation with escherichia coli gapdh reveals target for contraceptive design
    Journal of Biological Chemistry, 2009
    Co-Authors: Jan Frayne, Abby Taylor, Gus Cameron, Andrea T Hadfield
    Abstract:

    Sperm Glyceraldehyde-3-Phosphate Dehydrogenase has been shown to be a successful target for a non-hormonal contraceptive approach, but the agents tested to date have had unacceptable side effects. Obtaining the structure of the sperm-specific isoform to allow rational inhibitor design has therefore been a goal for a number of years but has proved intractable because of the insoluble nature of both native and recombinant protein. We have obtained soluble recombinant sperm Glyceraldehyde-3-Phosphate Dehydrogenase as a heterotetramer with the Escherichia coli Glyceraldehyde-3-Phosphate Dehydrogenase in a ratio of 1:3 and have solved the structure of the heterotetramer which we believe represents a novel strategy for structure determination of an insoluble protein. A structure was also obtained where Glyceraldehyde 3-Phosphate binds in the Ps pocket in the active site of the sperm enzyme subunit in the presence of NAD. Modeling and comparison of the structures of human somatic and sperm-specific Glyceraldehyde-3-Phosphate Dehydrogenase revealed few differences at the active site and hence rebut the long presumed structural specificity of 3-chlorolactaldehyde for the sperm isoform. The contraceptive activity of α-chlorohydrin and its apparent specificity for the sperm isoform in vivo are likely to be due to differences in metabolism to 3-chlorolactaldehyde in spermatozoa and somatic cells. However, further detailed analysis of the sperm Glyceraldehyde-3-Phosphate Dehydrogenase structure revealed sites in the enzyme that do show significant difference compared with published somatic Glyceraldehyde-3-Phosphate Dehydrogenase structures that could be exploited by structure-based drug design to identify leads for novel male contraceptives.

Gus Cameron - One of the best experts on this subject based on the ideXlab platform.

  • structure of insoluble rat sperm Glyceraldehyde 3 phosphate Dehydrogenase gapdh via heterotetramer formation with escherichia coli gapdh reveals target for contraceptive design
    Journal of Biological Chemistry, 2009
    Co-Authors: Jan Frayne, Abby Taylor, Gus Cameron, Andrea T Hadfield
    Abstract:

    Sperm Glyceraldehyde-3-Phosphate Dehydrogenase has been shown to be a successful target for a non-hormonal contraceptive approach, but the agents tested to date have had unacceptable side effects. Obtaining the structure of the sperm-specific isoform to allow rational inhibitor design has therefore been a goal for a number of years but has proved intractable because of the insoluble nature of both native and recombinant protein. We have obtained soluble recombinant sperm Glyceraldehyde-3-Phosphate Dehydrogenase as a heterotetramer with the Escherichia coli Glyceraldehyde-3-Phosphate Dehydrogenase in a ratio of 1:3 and have solved the structure of the heterotetramer which we believe represents a novel strategy for structure determination of an insoluble protein. A structure was also obtained where Glyceraldehyde 3-Phosphate binds in the Ps pocket in the active site of the sperm enzyme subunit in the presence of NAD. Modeling and comparison of the structures of human somatic and sperm-specific Glyceraldehyde-3-Phosphate Dehydrogenase revealed few differences at the active site and hence rebut the long presumed structural specificity of 3-chlorolactaldehyde for the sperm isoform. The contraceptive activity of α-chlorohydrin and its apparent specificity for the sperm isoform in vivo are likely to be due to differences in metabolism to 3-chlorolactaldehyde in spermatozoa and somatic cells. However, further detailed analysis of the sperm Glyceraldehyde-3-Phosphate Dehydrogenase structure revealed sites in the enzyme that do show significant difference compared with published somatic Glyceraldehyde-3-Phosphate Dehydrogenase structures that could be exploited by structure-based drug design to identify leads for novel male contraceptives.

Abby Taylor - One of the best experts on this subject based on the ideXlab platform.

  • structure of insoluble rat sperm Glyceraldehyde 3 phosphate Dehydrogenase gapdh via heterotetramer formation with escherichia coli gapdh reveals target for contraceptive design
    Journal of Biological Chemistry, 2009
    Co-Authors: Jan Frayne, Abby Taylor, Gus Cameron, Andrea T Hadfield
    Abstract:

    Sperm Glyceraldehyde-3-Phosphate Dehydrogenase has been shown to be a successful target for a non-hormonal contraceptive approach, but the agents tested to date have had unacceptable side effects. Obtaining the structure of the sperm-specific isoform to allow rational inhibitor design has therefore been a goal for a number of years but has proved intractable because of the insoluble nature of both native and recombinant protein. We have obtained soluble recombinant sperm Glyceraldehyde-3-Phosphate Dehydrogenase as a heterotetramer with the Escherichia coli Glyceraldehyde-3-Phosphate Dehydrogenase in a ratio of 1:3 and have solved the structure of the heterotetramer which we believe represents a novel strategy for structure determination of an insoluble protein. A structure was also obtained where Glyceraldehyde 3-Phosphate binds in the Ps pocket in the active site of the sperm enzyme subunit in the presence of NAD. Modeling and comparison of the structures of human somatic and sperm-specific Glyceraldehyde-3-Phosphate Dehydrogenase revealed few differences at the active site and hence rebut the long presumed structural specificity of 3-chlorolactaldehyde for the sperm isoform. The contraceptive activity of α-chlorohydrin and its apparent specificity for the sperm isoform in vivo are likely to be due to differences in metabolism to 3-chlorolactaldehyde in spermatozoa and somatic cells. However, further detailed analysis of the sperm Glyceraldehyde-3-Phosphate Dehydrogenase structure revealed sites in the enzyme that do show significant difference compared with published somatic Glyceraldehyde-3-Phosphate Dehydrogenase structures that could be exploited by structure-based drug design to identify leads for novel male contraceptives.

Vladimir I Muronetz - One of the best experts on this subject based on the ideXlab platform.

  • The activation of glycolysis performed by the non-phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase in the model system.
    Biochemical and Biophysical Research Communications, 2003
    Co-Authors: D.y Arutyunov, Vladimir I Muronetz
    Abstract:

    Influence of non-phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase (GAPN) on glycolysis was investigated. The addition of GAPN-which oxidizes Glyceraldehyde-3-Phosphate directly to the 3-phosphoglyceric acid-led to the strong increase in the rate of lactate accumulation in the rat muscle extract with low ADP content. The lactate accumulation was also observed in the presence of GAPN in rat muscle extract, which contained only ATP and no ADP. This can be the evidence of the "futile cycle" stimulated by GAPN. Here ADP can be regenerated from ATP by the phosphoglycerate kinase reaction. The high resistance of GAPN from Streptococcus mutans towards inactivation by natural oxidant-H(2)O(2) was showed. This feature distinguishes GAPN from phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase, which is very sensitive to modification by hydrogen peroxide. A possible role of the oxidants and non-phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase in the regulation of glycolysis is discussed.

  • Interaction between d-Glyceraldehyde-3-Phosphate Dehydrogenase and 3-phosphoglycerate kinase and its functional consequences
    FEBS Letters, 1992
    Co-Authors: Natalia A. Khoroshilova, Vladimir I Muronetz, Natalia K. Nagradova
    Abstract:

    Abstract E. Coli d -Glyceraldehyde-3-Phosphate Dehydrogenase covalently bound to Sepharose was shown to form a complex with soluble E. coli 3-phosphoglycerate kinase with a stoichiometry of 1.77±0.61 kinase molecules per tetramer of the Dehydrogenase and an apparent Kd of 1.03±0.68μM (10 mM sodium phosphate, 0.15 M NaCl). No interaction was detected between E. coli d -Glyceraldehyde-3-Phosphate Dehydrogenase and rabbit muscle 3-phosphoglycerate kinase. The species-specificity of the bienzyme association made it possible to develop a kinetic approach to demonstrate the functionally significant interaction between E. coli d -Glyceraldehyde-3-Phosphate Dehydrogenase and E. coli 3-phosphoglycerate kinase, which consists of an increase in steady-state rate of the coupled reaction.