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New insights into radical enzyme could lead to new medical therapies

by News Staff
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An international collaboration of scientists recently made significant strides in shedding light on a longstanding biological puzzle. Published in Science last week, their research delves into the complex realm of DNA building block formation, a process that has puzzled researchers for over half a century.

The study zeroes in on a critical player in this intricate process: the radical enzyme, a highly reactive molecule responsible for kickstarting DNA synthesis. Unveiling the secrets of ribonucleotide reductases (RNRs), a special class of enzymes crucial in creating DNA components, this research not only enriches our understanding of fundamental biology but also holds promise for potential medical and therapeutic breakthroughs, particularly in the fields of cancer and infectious diseases.

The team behind this breakthrough hails from diverse institutions, including Stockholm University, CNRS-University of Toulouse, the Department of Energy’s SLAC National Accelerator Laboratory, Lawrence Berkeley National Laboratory, and others, all pooling their expertise to crack the enigma of RNRs.

Paradoxical phenomenon

For decades, ribonucleotide reductases (RNRs) have baffled scientists with their dual role in generating free radicals – molecules known for causing cellular damage yet crucial in various biochemical processes. The key to unraveling the RNR mystery lies in comprehending their active radical state, a paradoxical phenomenon first uncovered half a century ago, where the protein itself becomes a radical, possessing an odd number of electrons.

Martin Högbom, a researcher from Stockholm University who led this groundbreaking work, expressed his amazement at enzymes utilizing radicals in their functions. He noted that the idea of visualizing a protein radical’s structure once seemed far-fetched but remained a persistent curiosity throughout his scientific career.

Over time, numerous enzyme systems have been recognized for employing radical chemistry. However, until now, researchers couldn’t observe the structure of proteins in this reactive state due to their vulnerability to radiation damage caused by X-ray beams.

Collaborating with SLAC scientist Roberto Alonso-Mori, the team harnessed the advanced capabilities of SLAC’s Linac Coherent Light Source (LCLS) X-ray laser. They employed a state-of-the-art technique called serial femtosecond crystallography, which enables the observation of proteins and molecules at their natural temperatures. This was coupled with diffraction-before-destruction, allowing precise data collection from delicate samples just before the laser obliterated them. Through these innovative methods, they successfully captured images of the protein in its active radical state, offering a direct glimpse into its functional behavior.

Therapeutic potential

The significance of this discovery extends beyond its fundamental implications in biology, as it holds the promise of therapeutic applications, particularly in the context of cell division, where RNR plays a crucial role.

Jan Kern, a collaborator from Berkeley Lab, emphasized the potential for medical advancements, stating, “This novel method empowers us to grasp the natural control and utilization of these reactive states, offering potential breakthroughs in treatments, especially for conditions such as cancer.”

Looking ahead, the researchers aspire to broaden their investigations to encompass various forms of this enzyme. Hugo Lebrette, a collaborator who previously conducted research at Stockholm University and is now a research group leader at the CNRS-University of Toulouse, expressed their goal to explore different types of ribonucleotide reductases. By comparing these variations, they hope to gain insights into targeting specific enzymes in relevant organisms, which could reshape disease treatment approaches.

Vivek Srinivas, a postdoctoral researcher at Stockholm University and a collaborator, added, “This opens the door to observing diverse proteins in their active states, with the potential to revolutionize disease treatment methods.”

It’s important to note that while the data collection phase was completed within an hour, the foundation for this significant achievement was laid over several decades. This journey involved meticulous groundwork, the identification of suitable model systems, and the preparation of samples.

Martin Högbom, who has been captivated by protein radicals for nearly three decades since his undergraduate studies, expressed the team’s mission to comprehensively understand this protein family. Each experiment and research paper contributes to their pursuit of this objective, and the latest results represent a substantial leap forward in their scientific journey.

Source: SLAC National Accelerator Laboratory

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