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Jan 30, 2014

Looking-Glass Nucleic Acid Zymes Promise RNA-Editing Wonderland

Looking-Glass Nucleic Acid Zymes Promise RNA-Editing Wonderland

Atomic models proposed for the L-hammerhead ribozyme and the L-DNAzyme interacting with their target D-RNA. [Volker A. Erdmann et al.]

  • Biological molecules “twist” in just one direction. How biological molecules settled on one direction over another is unknown; however, ever since the choices were made, they seem to have had the benefit of ensuring that biological molecules recognize each other with high specificity and fidelity.

    Occasionally, nature throws a curve—for example, proteins with reverse handedness are found in bacterial cell walls. Such curiosities intrigue scientists, who wonder what might happen if they were to experiment with biomolecules from the other side of the looking glass.

    A team of scientists led by Volker A. Erdmann at the Free University of Berlin report that they have succeeded for the first time in creating mirror-image enzymes—so-called Spiegelzymes—out of nucleic acids. It turns out that these enzymes can be used in living cells for the targeted cutting of natural nucleic acids. In other words, they can be used as molecular scissors. In addition, they appear to be extremely stable, and they do not appear to trigger side reactions of the immune system.

    The scientists published their results in an article published January 29 in PLOS ONE, in an article entitled “Mirror-Image Hammerhead Ribozymes and Mirror-Image DNAzymes, an Alternative to siRNAs and microRNAs to Cleave mRNAs In Vivo?” The article considers the possibility that mirror-image nucleic acid zymes could cut up individual nucleic acids responsible for human diseases and thus deactivate them.

    In their article, the authors write: “We performed extensive three-dimensional molecular modeling experiments with mirror-image hammerhead ribozymes and DNAzymes interacting with D-RNA targets.” Through the use of specially constructed mirror-image nucleic acid zymes, Erdmann and his team were able to inhibit the production of a green glowing protein in a cell model. The zymes cut the messenger RNA that coded for the protein.

    To account for these results, the authors propose a model in which L/D-double helix structures can be formed by natural Watson-Crick base pairs, but where the nucleosides of one of the two strands occur in an anticlinal conformation: “Interestingly enough, the duplexes (L-RNA/D-RNA and L-DNA/D-RNA) in these models can show either right- or left-handedness. This is a very new observation, suggesting that molecular symmetry of enantiomeric nucleic acids is broken down.”

    In their conclusions, the authors anticipate exploring the potential applications of nucleic acid zymes in those areas of molecular biology and molecular medicine in which naturally occurring RNA molecule sequences are employed, such as mRNAs, microRNAs, and siRNAs.



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