Abstract
Molecular modelling and synthetic studies have been carried out on tyrosinyl adenylate and analogues to probe the interactions seen in the active site of the X-ray crystal structure of tyrosyl tRNA synthetase from Bacillus stearothermophilus, and to search for new inhibitors of this enzyme. Micromolar and sub-micromolar inhibitors of tyrosyl tRNA synthetases from both B. stearothermophilus and Staphylococcus aureus have been synthesised. The importance of the adenine ring to the binding of tyrosinyl adenylate to the enzyme, and the importance of water-mediated hydrogen bonding interactions, have been highlighted. The inhibition data has been further supported by homology modelling with the S. aureus enzyme, and by ligand docking studies.
MeSH terms
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Adenine / metabolism
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Adenosine Monophosphate / analogs & derivatives*
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Adenosine Monophosphate / chemistry
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Adenosine Monophosphate / metabolism
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Amino Acid Sequence
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Binding Sites
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Geobacillus stearothermophilus / enzymology*
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Geobacillus stearothermophilus / genetics
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Models, Molecular
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Molecular Sequence Data
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Phosphates / metabolism
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Protein Binding
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Ribose / metabolism
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Sequence Homology, Amino Acid
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Staphylococcus aureus / enzymology
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Staphylococcus aureus / genetics
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Tyrosine / analogs & derivatives*
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Tyrosine / chemistry
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Tyrosine / metabolism
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Tyrosine-tRNA Ligase / antagonists & inhibitors
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Tyrosine-tRNA Ligase / genetics
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Tyrosine-tRNA Ligase / metabolism*
Substances
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Enzyme Inhibitors
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Phosphates
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Adenosine Monophosphate
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Tyrosine
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tyrosinyl-5'-AMP
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Ribose
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Tyrosine-tRNA Ligase
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Adenine