Researchers led by chemist Claudia Höbartner have now uncovered the 3D structure of the RNA enzyme SAMURI. Their study provides insights into the development of ribozymes and the evolution of catalytically active RNA.
RNA molecules are an integral part of the human body: In cells, they ensure the transfer of genetic information and regulate the activity of genes. Some even act as catalysts, allowing chemical reactions to take place that would otherwise take place very slowly or not at all. Enzymes made of RNA are called "ribozymes".
A group of researchers led by Professor Claudia Höbartner at the University of Würburg (JMU) has now uncovered the three-dimensional structure of a very special ribozyme: SAMURI. This is an RNA molecule generated in the lab that the team first presented in 2023 . The researchers from the Institute of Organic Chemistry were able to determine the 3D structure of SAMURI using X-ray crystallography and in collaboration with Professor Hermann Schindelin from the Rudolf Virchow Centre in Würzburg.
Small Changes with a Big Impact
What makes SAMURI so interesting for the researchers is its very special ability: the ribozyme can chemically modify other RNA molecules at a specific site and thus influence their function - for example, activate them or render them recognisable by proteins. Such modifications have some very important tasks in nature and ensure that RNAs can carry out their function properly. If errors occur in this regulation, i.e. if an RNA has too many or too few chemical changes, this can lead to the failure of certain metabolic processes.
"We can think of RNA molecules as sentences made up of individual words and letters (nucleosides)", explains Höbartner. "The smallest changes at individual points - such as the replacement of a letter - can completely change the meaning of a word or the entire sentence. Just as the word "bat" becomes "cat" by changing a letter, thus describing two distinct animals with very different abilities, it is similar at the cellular level: "Here, the RNA receives the new information by nature making small chemical changes to it. In science, these are called modifications. Enzymes carry out a chemical reaction on the RNA, using a helper molecule called S-adenosylmethionine, or SAM for short, which is important for many processes in the cell."
SAMURI also uses SAM to introduce modifications in the RNA. It is exciting to note that some natural RNA molecules discovered in bacteria can also interact with SAM - but without catalysing the chemical reaction. These RNAs are called riboswitches, and they do not chemically modify other RNAs.
Thanks to the deciphered molecular structure of SAMURI, the researchers can now better answer the question of how the specific interaction of artificial ribozymes with SAM differ from natural riboswitches. Studies suggest that naturally occurring SAM-binding RNA could be derived from earlier ribozymes that lost their catalytic function during evolution", says Höbartner.
Basic Research Guides the Development of New Therapeutic Strategies
Knowledge of the structure and function of catalytic RNA is important for improving existing ribozymes and developing new ones. For example, it would be important for research into natural RNA modifications - for example, to visualise them, but also for their use in therapeutic RNAs.
"Our findings could therefore provide new directions for the development of RNA-based therapeutics" says Höbartner. "It is conceivable that further developed ribozymes could one day be used as drugs themselves."
The work was funded by the German Research Foundation (DFG).
About the Study
Structure and catalytic activity of the SAM-utilising ribozyme SAMURI. Hsuan-Ai Chen, Takumi Okuda, Ann-Kathrin Lenz, Carolin P. M. Scheitl, Hermann Schindelin & Claudia Höbartner. Published on 8 January 2025. DOI: 10.1038/s41589-024-01808-w
