UC Irvine-led team engineers new enzyme to produce synthetic genetic material

A research team led by the University of California, Irvine has engineered an efficient new enzyme that can produce a synthetic genetic material called threose nucleic acid. The ability to synthesize artificial chains of TNA, which is inherently more stable than DNA, advances the discovery of potentially more powerful, precise therapeutic options to treat cancer and autoimmune, metabolic and infectious diseases.

A paper recently published in Nature Catalysis describes how the team created an enzyme called 10-92 that achieves faithful and fast TNA synthesis, overcoming key challenges in previous enzyme design strategies. Inching ever closer to the capability of natural DNA synthesis, the 10-92 TNA polymerase facilitates the development of future TNA drugs.

DNA polymerases are enzymes that replicate organisms’ genomes by accurately and efficiently copying DNA. They play vital roles in biotechnology and healthcare, as seen in the fight against COVID-19, in which they were crucial to pathogen detection and eventual treatment using the mRNA vaccine.

“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 corresponding author John Chaput, UC Irvine professor of pharmaceutical sciences. “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 team produced the 10-92 TNA polymerase using a technique called homologous recombination, which rearranges polymerase fragments from related species of archaebacteria. Through repeated cycles of evolution, the researchers identified polymerase variants with increasing activity, ultimately resulting in a variant that’s within the range of natural enzymes.

“Drugs of the future could look very different than those we use today,” Chaput said. “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. 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.”

Other UC Irvine team members were 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 – all from the Department of Pharmaceutical Sciences.

This work was supported by a grant from the National Science Foundation, under award MCB1946312. John Chaput, Victoria Maola, Eric Yik and UC Irvine have filed a patent application (PCT/US24/1159) on the composition and activity of the 10-92 TNA polymerase. The other authors declared no competing interests.

UC Irvine’s Brilliant Future campaign: Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for the university. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UC Irvine seeks to reach new heights of excellence in student success, health and wellness, research and more. The School of Pharmacy & Pharmaceutical Sciences plays a vital role in the success of the campaign. Learn more by visiting https://brilliantfuture.uci.edu/school-of-pharmacy-and-pharmaceutical-sciences.

About the University of California, Irvine: Founded in 1965, UC Irvine is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UC Irvine has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UC Irvine, visit www.uci.edu.

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Journal Reference:

Victoria A. Maola, Eric J. Yik, Mohammad Hajjar, Joy J. Lee, Manuel J. Holguin, Riley N. Quijano, Kalvin K. Nguyen, Katherine L. Ho, Jenny V. Medina, Nicholas Chim, John C. Chaput. Directed evolution of a highly efficient TNA polymerase achieved by homologous recombination. Nature Catalysis, 2024; DOI: 10.1038/s41929-024-01233-1