RNA, or ribonucleic acid, plays a fundamental role in the biology of living organisms, including humans. As a crucial molecule within cells, RNA performs several vital functions, including the transfer of genetic information from DNA to proteins, and regulating gene activity. Yet its impact goes beyond that; some RNA molecules can even catalyze chemical reactions, serving as enzymes in cellular processes. These RNA-based enzymes are called “ribozymes.”
Ribozymes are fascinating because they hold the ability to catalyze chemical reactions in a way similar to protein enzymes, but with the inherent flexibility and adaptability of RNA. This discovery reshaped the conventional view that only proteins could serve as catalysts in biological processes. Ribozymes are now known to play roles in gene regulation and a variety of other functions.
In a significant breakthrough, a team of researchers led by Professor Claudia Höbartner from the University of Würzburg (JMU) have unveiled the three-dimensional structure of a special ribozyme called SAMURI. Their discovery, published in Nature Chemical Biology, offers deep insights into how this RNA molecule works, how it chemically modifies other RNA molecules, and what its discovery could mean for medical applications.
Unveiling SAMURI: A Special Ribozymic Discovery
SAMURI, a ribozyme engineered in the laboratory, is part of a long-standing area of interest in molecular biology: catalytic RNA. In 2023, Professor Höbartner and her team presented SAMURI, which was created in the lab to showcase how a particular RNA can perform a delicate chemical modification. The modification SAMURI carries out on RNA molecules has broad implications for understanding gene expression regulation, and how small changes to the molecular structure of RNA can significantly alter its biological function.
Using advanced X-ray crystallography in collaboration with Professor Hermann Schindelin from the Rudolf Virchow Centre in Würzburg, the researchers were able to determine the three-dimensional structure of SAMURI, a critical step in understanding its precise mode of action. X-ray crystallography allowed them to explore the intricate atomic interactions within the RNA molecule, providing a detailed map of its architecture. This is essential because knowing the shape of an RNA molecule is often the key to deciphering how it works at a biochemical level.
SAMURI’s Unique Ability to Modify RNA
The most striking aspect of SAMURI’s functionality is its ability to chemically modify RNA at specific sites, which can then alter how the RNA molecule behaves. These modifications can help activate the RNA or enable it to bind to proteins that would otherwise ignore it. Such modifications are essential for regulating RNA function in living cells.
The introduction of small chemical changes in RNA allows it to participate in diverse and essential cellular tasks. For instance, adding or removing specific chemical groups can control whether RNA is stabilized or degraded, whether it can participate in protein production, or whether it can interact with other biomolecules. These modifications are crucial for the proper functioning of cellular mechanisms, ensuring that genes are expressed at the right time and in the right amounts.
Höbartner explained this concept using a metaphor from language: just as changing a letter in a word can alter its meaning, small chemical changes in RNA can significantly shift its function. For example, changing the letter ‘b’ in “bat” to an ‘c’ results in the word “cat,” representing two distinct animals with different capabilities. Similarly, small alterations in RNA sequences result in different biological functions, which are essential for the body’s complex systems.
The Role of S-Adenosylmethionine (SAM) in RNA Modifications
SAMURI, like natural enzymes involved in RNA modification, relies on a small molecule called S-adenosylmethionine (SAM) to introduce these changes. SAM is a critical cofactor in numerous cellular processes, many of which involve modifying the structure and function of RNA molecules. SAM acts as a chemical donor, supplying the necessary atoms and groups to modify RNA molecules.
Interestingly, some naturally occurring RNA molecules in bacteria also interact with SAM, but they do so without catalyzing a chemical reaction. These RNAs, known as riboswitches, use SAM to regulate their activity by changing their shape upon binding to the molecule. However, riboswitches do not chemically modify other RNAs; they simply react to the presence of SAM by altering their structure, which can affect gene expression or other cellular functions.
The distinction between SAMURI and natural riboswitches lies in their catalytic abilities. SAMURI not only binds SAM but also uses it to directly modify other RNA molecules. This distinction opens new avenues for understanding how ribozymes evolved and could help illuminate how cellular systems exploit RNA-based catalysis. The ability to catalyze these modifications was likely a key feature of ribozymes early in evolutionary history, providing insight into how natural riboswitches may have once had catalytic functions but lost them over time.
Potential for RNA-Based Therapeutics
The findings of the research team, particularly the detailed molecular structure of SAMURI, have far-reaching implications for the development of RNA-based therapies. Understanding the structure-function relationship of ribozymes could allow scientists to engineer new RNA molecules capable of precise chemical modifications that can be harnessed for therapeutic purposes. Such discoveries contribute to the expanding field of RNA-based therapeutics, which holds tremendous potential for treating diseases linked to genetic mutations or faulty gene regulation.
Many current and emerging therapeutic approaches, such as gene therapies and RNA vaccines, work by manipulating RNA molecules in various ways to either correct genetic errors or induce specific immune responses. By providing new insight into the chemical modifications that RNA undergoes naturally, scientists can design new molecules or small RNA sequences that directly target or modify disease-related RNA. The ultimate goal would be to design therapeutic ribozymes that not only modify the expression of defective genes but also serve as precise molecular tools to correct the underlying biological defects responsible for various illnesses.
As Professor Höbartner notes, the new insights into ribozymes like SAMURI provide exciting possibilities for therapeutic applications, including potentially designing drug-like RNA molecules. By harnessing the natural catalysis of ribozymes, future treatments might be able to specifically and efficiently target genetic material for corrections, perhaps offering new hope for the treatment of complex diseases such as cancer, viral infections, or genetic disorders.
Ribozymes and the Future of Drug Development
Ribozymes and their catalytic abilities have been the subject of significant research since their discovery in the 1980s. With the advent of structural studies like the one conducted on SAMURI, we now have a more detailed understanding of how these RNA molecules function at the atomic level. The more we learn about these complex molecules, the greater potential there is for their application in biotechnological innovations and medical treatments.
For example, enhanced ribozymes could be developed to target and cut out defective segments of RNA in a controlled manner, offering an alternative to traditional gene editing technologies. These ribozymes could potentially serve as novel delivery vehicles for correcting genetic mutations or adjusting the gene expression of certain proteins implicated in diseases. Moreover, RNA-based enzymes can provide a quicker and more efficient means of therapeutic interventions compared to some protein-based methods.
Further research into SAMURI’s structural and functional properties may help in developing such RNA therapeutics. The greater the understanding of the processes by which ribozymes like SAMURI act—modifying RNA and potentially providing new avenues for treatment—the more likely it becomes that RNA-based drugs could be designed and synthesized. Researchers are already exploring RNA-based treatments for a variety of diseases, and future advances could revolutionize how we approach genetic disorders, cancer, and other conditions related to faulty RNA processing.
Reference: Hsuan-Ai Chen et al, Structure and catalytic activity of the SAM-utilizing ribozyme SAMURI, Nature Chemical Biology (2025). DOI: 10.1038/s41589-024-01808-w