A team of researchers from the University of California, Irvine has successfully developed a highly efficient enzyme capable of generating a synthetic genetic material known as threose nucleic acid (TNA). The new ability to create TNA, which is more stable than DNA, enhances the exploration of innovative therapeutic strategies to combat cancer, autoimmune diseases, metabolic disorders, and infections.
A recent study published in Nature Catalysis explains how the team engineered an enzyme named 10-92 that enables quick and accurate synthesis of TNA, addressing significant obstacles faced in earlier enzyme development efforts. With this advancement, the team is getting closer to matching the efficiency of natural DNA synthesis, paving the way for future TNA-based medications.
DNA polymerases are vital enzymes that duplicate an organism’s genetic material by accurately copying DNA. These enzymes are crucial in biotechnology and healthcare, underscored by their essential role in combating COVID-19 through pathogen detection and the development of mRNA vaccines for treatment.
“This breakthrough marks a significant advancement in synthetic biology and creates exciting opportunities for new medical applications by greatly reducing the performance differences between natural and synthetic enzyme systems,” said John Chaput, the lead researcher and professor of pharmaceutical sciences at UC Irvine. “TNA’s higher stability compared to DNA allows it to be utilized in a wider array of treatments, and the new 10-92 TNA polymerase will help us achieve this potential.”
The researchers produced the 10-92 TNA polymerase utilizing a method called homologous recombination, which rearranges polymerase fragments from similar types of archaebacteria. After multiple rounds of evolution, the team isolated polymerase variants with progressively better activity, ultimately developing one that operates within the range of natural enzymes.
“Future medications could differ significantly from those currently in use,” Chaput commented. “Given TNA’s resistance to enzymatic and chemical breakdown, it stands out as an excellent candidate for the development of new therapies, such as therapeutic aptamers, a promising class of drugs that attach to target molecules with high precision. Creating enzymes to enable these innovative approaches may overcome some limitations of antibodies, such as enhancing tissue penetration, thereby positively influencing human health.”
Other team members from UC Irvine included 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 research was made possible with funding from the National Science Foundation, under grant award MCB1946312. John Chaput, Victoria Maola, and Eric Yik, along with the University of California, Irvine, have submitted a patent application (PCT/US24/1159) concerning the composition and function of the 10-92 TNA polymerase. No competing interests were declared by the other authors.
