Proceedings of the National Academy of Sciences · 1999 · 117 citations · 34 references
Life SciencesBiochemistryMolecular BiologyDrug DiscoveryEnzymologyRna ProcessingEnzyme InhibitionRibosomal Rna ProcessingRna ChemistryRna CleavageRna InterferenceRna-protein InteractionsHammerhead Ribozyme CleavageHammerhead RibozymesMetal-mediated Rna CleavageRibonucleotide ChemistryRibozyme-mediated CleavageRibozymesTransfer Rna Cleavage
A number of aminoglycosides have been reported to interact and interfere with the function of various RNA molecules. Among these are 16S rRNA, the group I intron, and the hammerhead ribozymes. In this report we show that cleavage by RNase P RNA in the absence as well as in the presence of the RNase P protein is inhibited by several aminoglycosides. Among the ones we tested, neomycin B was found to be the strongest inhibitor with a Ki value in the micromolar range (35 microM). Studies of lead(II)-induced cleavage of RNase P RNA suggested that binding of neomycin B interfered with the binding of divalent metal ions to the RNA. Taken together, our findings suggest that aminoglycosides compete with Mg2+ ions for functionally important divalent metal ion binding sites. Thus, RNase P, which is an essential enzyme, is indeed a potential drug target that can be used to develop new drugs by using various aminoglycosides as lead compounds.
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The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme
Cecilia Guerrier-Takada, Katheleen Gardiner, Norman R. Pace et al. · Cell · 1983 · 2.7K citations