Synthesis of phosphonate analogues of ribose 1,5-bisphosphate and their effect on phosphofructokinase and fructose bisphosphatase.
Item
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Title
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Synthesis of phosphonate analogues of ribose 1,5-bisphosphate and their effect on phosphofructokinase and fructose bisphosphatase.
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Identifier
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AAI9315485
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identifier
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9315485
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Creator
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Linn, Gregory Saul.
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Contributor
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Adviser: Horst Schulz
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Date
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1993
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry | Chemistry, Organic | Chemistry, Pharmaceutical
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Abstract
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Phosphonate analogues of {dollar}\alpha{dollar}- and {dollar}\beta{dollar}-ribose 1,5-bisphosphate, in which the anomeric oxygen has been replaced by carbon, have been prepared in a multistep synthesis. The specific anomeric configuration of these purified compounds was determined using proton nuclear magnetic resonance and by analyzing fragments by mass spectrometry.;These analogues and {dollar}\alpha{dollar}-ribose 1,5-bisphosphate were tested as effectors of rabbit muscle 6-phosphofructo-1-kinase and rat liver fructose 1,6-bisphosphatase. {dollar}\alpha{dollar}-Ribose 1,5-bisphosphate and the {dollar}\alpha{dollar}- and {dollar}\beta{dollar}-anomer bisphosphonate analogues activated 6-phosphofructo-1-kinase, with {dollar}\alpha{dollar}-ribose 1,5-bisphosphate activating the enzyme to its V{dollar}\sb{lcub}\rm max{rcub}{dollar} and the {dollar}\alpha{dollar}- and {dollar}\beta{dollar}-anomer analogues activating the enzyme to 80% and 30% of its V{dollar}\sb{lcub}\rm max{rcub},{dollar} respectively. These results suggest that the analogues bind simultaneously to the allosteric and substrate sites. {dollar}\alpha{dollar}-Ribose 1,5-bisphosphate and the {dollar}\alpha{dollar}-anomer analogue inhibited fructose 1,6-bisphosphate non-competitively and did not potentiate adenosine monophosphate inhibition of this enzyme. The {dollar}\beta{dollar}-anomer analogue did not inhibit the enzyme even at a high concentration ({dollar}>{dollar}1 mM). These results are consistent with inhibition occurring at a site distinct from the substrate or adenosine monophosphate allosteric site. However, in light of recent findings (Liang et al., 1992; see bibliography), this inhibition can be rationalized by binding of the former two compounds to either the adenosine monophosphate binding site or the substrate site.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
