Published in 'Nature Catalysis', the study highlights the creation of an enzyme called 10-92, designed to overcome obstacles faced in previous enzyme engineering efforts. This enzyme efficiently synthesizes TNA, offering capabilities approaching those of natural DNA polymerases.
DNA polymerases are crucial for replicating genomes by accurately copying DNA, and their role has been vital in biotechnology, such as during the COVID-19 pandemic, where they were key to pathogen detection and the development of mRNA vaccines.
"This achievement represents a major milestone in the evolution of synthetic biology and opens up exciting possibilities for new therapeutic applications by significantly narrowing the performance gap between natural and artificial enzyme systems," said John Chaput, UC Irvine professor of pharmaceutical sciences and corresponding author. "Unlike DNA, TNA's biostability allows it to be used in a much broader range of treatments, and the new 10-92 TNA polymerase will enable us to reach that goal."
The 10-92 TNA polymerase was created using homologous recombination, a technique that rearranges polymerase fragments from related archaebacterial species. The enzyme was fine-tuned through repeated cycles of evolution, resulting in a highly active variant similar to natural enzymes.
"TNA's resilience to enzymatic and chemical degradation positions it as the ideal candidate for developing new treatments such as therapeutic aptamers, a promising drug class that binds to target molecules with high specificity," Chaput explained. "Engineering enzymes that facilitate the discovery of new approaches could address the limitations of antibodies, such as improved tissue penetration, and potentially have an even greater positive impact on human health."
Contributors to the research include UC Irvine graduate students Victoria A. Maola, Eric J. Yik, and Mohammad Hajjar; project scientist Nicholas Chim; and undergraduates Joy J. Lee, Kalvin K. Nguyen, Jenny V. Medina, Riley N. Quijano, Manuel J. Holguin, and Katherine L. Ho from the Department of Pharmaceutical Sciences.
The project was supported by a National Science Foundation grant under award MCB1946312. John Chaput, Victoria Maola, Eric Yik, and UC Irvine have filed a patent application (PCT/US24/1159) for the 10-92 TNA polymerase. The other authors have declared no competing interests.
Research Report:Directed evolution of a highly efficient TNA polymerase achieved by homologous recombination
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