Researchers at the University of Fribourg, in collaboration with partners from the Dubochet Centre for Imaging and EPFL, have unravelled a key mechanism of a vital human enzyme. The enzyme cystathionine beta-synthase (CBS) plays a crucial role in numerous processes within the body. Disruptions to its function are associated with the rare inherited disorder homocystinuria, various types of cancer and Down’s syndrome.

Enzymes carry out countless tasks within our cells. They ensure that vital substances are synthesised, converted and recycled. CBS is one of these vital helpers. The enzyme is involved in the breakdown of certain protein building blocks and contributes to the formation of hydrogen sulphide, a smelly gaseous substance that acts as a messenger in the body in small quantities.

If CBS does not function properly, this can have serious consequences. Insufficient enzyme activity can lead to the rare inherited disorder homocystinuria, whilst excessive activity is linked to various types of cancer and metabolic disorders.

CBS does not work alone
The study, now published in Nature Communications, shows that CBS does not simply exist as a single molecule within the cell. Instead, it can join with other CBS molecules to form long chains. Depending on how these chains are structured, the enzyme’s activity and stability change.

«CBS behaves like a molecular transformer,»explains study leader Dr. Tomas Majtan from the University of Fribourg. «It can alter its structure and adapt to different conditions within the cell. These changes directly influence how well the enzyme functions.»

The results also show that proteins are significantly more dynamic than had long been assumed. Rather than rigid building blocks, they are flexible structures that respond to signals from their environment and can adapt their behaviour accordingly.

Three states, three functions
Using state-of-the-art cryo-electron microscopy, the researchers were able to observe three different states of CBS. In its basic form, the enzyme is functional but operates at a normal level. Under certain conditions, it assumes a more stable form without becoming any more active. Only when an endogenous activator called S-adenosylmethionine binds to CBS does the enzyme form a larger structure and reach its highest level of activity.

The study thus demonstrates that it is not only the presence of a signal that is crucial, but also its precise nature. Small differences can determine whether CBS merely becomes more stable or actually increases its activity.

Longer lifespan through chain formation
Experiments in living cells also show that the formation of these chains offers a significant advantage. As a result, CBS remains stable and functional for longer. Variants of the enzyme that cannot form such structures are broken down more quickly and lose their function sooner.

The researchers also observed that the filament-forming forms tend to localise near the cell nucleus, whilst other forms are more widely distributed throughout the cell. This suggests that the organisation of the enzyme also influences its functions within the cell.

New prospects for medicine
The findings could be of great significance for the development of new therapies. Some disease-causing genetic mutations are located precisely in the regions of the enzyme responsible for chain formation. This suggests that diseases arise not only because the enzyme itself is impaired, but also because it can no longer adopt its correct form.

Future medicines could therefore aim to stabilise the healthy form of CBS or help the enzyme to assemble correctly. This could lead to new treatment approaches for homocystinuria, certain types of cancer and other conditions.

A better understanding for future therapies
Through their work, the researchers provide important new insights into the functioning of an enzyme that is of great significance to human health. The study demonstrates how closely a protein’s structure is linked to its function and opens up new possibilities for treating diseases through targeted interventions in these structures.
 

Link to the study: https://doi.org/10.1038/s41467-026-73198-7