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Finian J. Leeper - One of the best experts on this subject based on the ideXlab platform.
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probing riboswitch ligand interactions using Thiamine Pyrophosphate analogues
Organic and Biomolecular Chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Jason Micklefield, Kwasi Agyeiowusu, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Probing riboswitch–ligand interactions using Thiamine Pyrophosphate analogues
Organic & biomolecular chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Kwasi Agyei-owusu, Jason Micklefield, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Identification of novel ligands for Thiamine Pyrophosphate (TPP) riboswitches.
Biochemical Society transactions, 2011Co-Authors: Elena Cressina, Finian J. Leeper, Liuhong Chen, Michael Moulin, Chris Abell, Alison G. SmithAbstract:Riboswitches are regions of mRNA to which a metabolite binds in the absence of proteins, resoulting in alteration of transcription, translation or splicing. The most widespread forms of riboswitches are those responsive to TPP (Thiamine Pyrophosphate) the active form of vitamin B 1 , Thiamine. TPP-riboswitches have been found in all bacterial genomes examined, and are the only ones found in eukaryotes. In each case, the riboswitch appears to regulate the expression of a gene involved in synthesis or uptake of the vitamin. Riboswitches offer an attractive target for chemical intervention, and identification of novel ligands would allow a detailed study on structure–activity relationships, as well as potential leads for the development of antimicrobial compounds. To this end, we have developed a medium-throughput methodology for screening libraries of small molecules using biophysical methods.
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Synthesis and biological evaluation of Pyrophosphate mimics of Thiamine Pyrophosphate based on a triazole scaffold.
Organic & biomolecular chemistry, 2008Co-Authors: Karl M. Erixon, Chester L. Dabalos, Finian J. LeeperAbstract:Novel triazole-based Pyrophosphate analogues of Thiamine Pyrophosphate (TPP) have been synthesised and tested for inhibition of pyruvate decarboxylase (PDC) from Zymomonas mobilis. The thiazolium ring of Thiamine was replaced by a triazole in an efficient two-step procedure. Pyrophosphorylation then gave extremely potent triazole inhibitors with KI values down to 20 pM, compared to a KD value of 0.35 μM for TPP. This triazole scaffold was used for further investigation and six analogues containing mimics of the Pyrophosphate group were synthesised and tested for inhibition of PDC. Several effective analogues were found with KI values down to around 1 nM.
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Inhibition of pyruvate decarboxylase from Z. mobilis by novel analogues of Thiamine Pyrophosphate: investigating Pyrophosphate mimics
Chemical communications (Cambridge England), 2006Co-Authors: Karl M. Erixon, Chester L. Dabalos, Finian J. LeeperAbstract:Replacement of the thiazolium ring of Thiamine Pyrophosphate with a triazole gives extremely potent inhibitors of pyruvate decarboxylase from Z. mobilis, with KI values down to 20 pM; this system was used to explore Pyrophosphate mimics and several effective analogues were discovered.
Diana M Downs - One of the best experts on this subject based on the ideXlab platform.
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thibpq encodes an abc transporter required for transport of Thiamine and Thiamine Pyrophosphate in salmonella typhimurium
Journal of Biological Chemistry, 1998Co-Authors: Eric Webb, K R Claas, Diana M DownsAbstract:Abstract In Salmonella typhimurium, Thiamine Pyrophosphate (TPP) is a required cofactor for several enzymes in central metabolism. Herein we identify a new thi operon,thiBPQ (designated sfuABC in Escherichia coli), required for the transport of Thiamine and TPP into the cell. Insertions in the operon result in strains that are phenotypically and biochemically defective in Thiamine and TPP transport. Data presented herein show that this operon is transcriptionally repressed in the presence of exogenous Thiamine, with TPP the likely regulatory molecule. This work represents the first identification of Thiamine transport genes in bacteria and demonstrates the function of a proposed ABC transporter in E. coli.
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Thiamine Pyrophosphate tpp negatively regulates transcription of some thi genes of salmonella typhimurium
Journal of Bacteriology, 1996Co-Authors: Eric Webb, F Febres, Diana M DownsAbstract:In Salmonella typhimurium, Thiamine is a required nutrient that is synthesized de novo. Labeling studies have demonstrated probable precursors for both the 4-amino-5-hydroxymethyl-2-methylpyrimidine Pyrophosphate moiety and the 4-methyl-5-(beta-hydroxyethyl) thiazole monophosphate moiety. The isolation of Thiamine auxotrophs with mutations in at least five different genetic loci is reported. The majority (22 of 25) of the mutants required only the thiazole moiety of Thiamine to satisfy their growth requirement. Most (14 of 25) of the mutants were affected in the thi cluster at min 90 on the S. typhimurium genetic map. Data provided herein indicate that this cluster encodes an operon whose transcription is regulated by Thiamine and suggest that Thiamine Pyrophosphate, or a molecule derived form it, is the effector molecule. Mutants with altered regulation of this operon were isolated, and we propose that they are defective in Thiamine phosphate kinase, the product of the thiL gene.
Alison G. Smith - One of the best experts on this subject based on the ideXlab platform.
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probing riboswitch ligand interactions using Thiamine Pyrophosphate analogues
Organic and Biomolecular Chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Jason Micklefield, Kwasi Agyeiowusu, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Probing riboswitch–ligand interactions using Thiamine Pyrophosphate analogues
Organic & biomolecular chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Kwasi Agyei-owusu, Jason Micklefield, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Identification of novel ligands for Thiamine Pyrophosphate (TPP) riboswitches.
Biochemical Society transactions, 2011Co-Authors: Elena Cressina, Finian J. Leeper, Liuhong Chen, Michael Moulin, Chris Abell, Alison G. SmithAbstract:Riboswitches are regions of mRNA to which a metabolite binds in the absence of proteins, resoulting in alteration of transcription, translation or splicing. The most widespread forms of riboswitches are those responsive to TPP (Thiamine Pyrophosphate) the active form of vitamin B 1 , Thiamine. TPP-riboswitches have been found in all bacterial genomes examined, and are the only ones found in eukaryotes. In each case, the riboswitch appears to regulate the expression of a gene involved in synthesis or uptake of the vitamin. Riboswitches offer an attractive target for chemical intervention, and identification of novel ligands would allow a detailed study on structure–activity relationships, as well as potential leads for the development of antimicrobial compounds. To this end, we have developed a medium-throughput methodology for screening libraries of small molecules using biophysical methods.
Liuhong Chen - One of the best experts on this subject based on the ideXlab platform.
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probing riboswitch ligand interactions using Thiamine Pyrophosphate analogues
Organic and Biomolecular Chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Jason Micklefield, Kwasi Agyeiowusu, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Probing riboswitch–ligand interactions using Thiamine Pyrophosphate analogues
Organic & biomolecular chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Kwasi Agyei-owusu, Jason Micklefield, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Identification of novel ligands for Thiamine Pyrophosphate (TPP) riboswitches.
Biochemical Society transactions, 2011Co-Authors: Elena Cressina, Finian J. Leeper, Liuhong Chen, Michael Moulin, Chris Abell, Alison G. SmithAbstract:Riboswitches are regions of mRNA to which a metabolite binds in the absence of proteins, resoulting in alteration of transcription, translation or splicing. The most widespread forms of riboswitches are those responsive to TPP (Thiamine Pyrophosphate) the active form of vitamin B 1 , Thiamine. TPP-riboswitches have been found in all bacterial genomes examined, and are the only ones found in eukaryotes. In each case, the riboswitch appears to regulate the expression of a gene involved in synthesis or uptake of the vitamin. Riboswitches offer an attractive target for chemical intervention, and identification of novel ligands would allow a detailed study on structure–activity relationships, as well as potential leads for the development of antimicrobial compounds. To this end, we have developed a medium-throughput methodology for screening libraries of small molecules using biophysical methods.
Elena Cressina - One of the best experts on this subject based on the ideXlab platform.
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probing riboswitch ligand interactions using Thiamine Pyrophosphate analogues
Organic and Biomolecular Chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Jason Micklefield, Kwasi Agyeiowusu, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Probing riboswitch–ligand interactions using Thiamine Pyrophosphate analogues
Organic & biomolecular chemistry, 2012Co-Authors: Liuhong Chen, Karl M. Erixon, Elena Cressina, Chris Abell, Alison G. Smith, Neil Dixon, Kwasi Agyei-owusu, Jason Micklefield, Finian J. LeeperAbstract:The Escherichia coli thiM riboswitch forms specific contacts with its natural ligand, Thiamine Pyrophosphate (TPP or Thiamine diphosphate), allowing it to generate not only nanomolar binding affinity, but also a high degree of discrimination against similar small molecules. A range of synthetic TPP analogues have been used to probe each of the riboswitch–ligand interactions. The results show that the pyrimidine-sensing helix of thiM is exquisitely tuned to select for TPP by recognising the H-bonding donor and acceptors around its aminopyrimidine ring and also by forming π-stacking interactions that may be sensitive to the electronics of the ring. The central thiazolium ring of TPP appears to be more important for ligand recognition than previously thought. It may contribute to binding via long-range electrostatic interactions and/or by exerting an electron withdrawing effect on the pyrimidine ring, allowing its presence to be sensed indirectly and thereby allowing discrimination between Thiamine (and its phosphate esters) and other aminopyrimidines found in vivo. The Pyrophosphate moiety is essential for submicromolar binding affinity, but unexpectedly, it does not appear to be strictly necessary for modulation of gene expression.
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Identification of novel ligands for Thiamine Pyrophosphate (TPP) riboswitches.
Biochemical Society transactions, 2011Co-Authors: Elena Cressina, Finian J. Leeper, Liuhong Chen, Michael Moulin, Chris Abell, Alison G. SmithAbstract:Riboswitches are regions of mRNA to which a metabolite binds in the absence of proteins, resoulting in alteration of transcription, translation or splicing. The most widespread forms of riboswitches are those responsive to TPP (Thiamine Pyrophosphate) the active form of vitamin B 1 , Thiamine. TPP-riboswitches have been found in all bacterial genomes examined, and are the only ones found in eukaryotes. In each case, the riboswitch appears to regulate the expression of a gene involved in synthesis or uptake of the vitamin. Riboswitches offer an attractive target for chemical intervention, and identification of novel ligands would allow a detailed study on structure–activity relationships, as well as potential leads for the development of antimicrobial compounds. To this end, we have developed a medium-throughput methodology for screening libraries of small molecules using biophysical methods.