Sweet seduction is omnipresent, whether it’s the lure of jam at breakfast in the morning or the chocolate that beckons us in the evening. We are all familiar with the frustration at the end of the day from having succumbed to these sweet temptations. After all, experts agree that sugar is bad for you.

It’s easy to think that sugar’s role in our lives is limited to it being a source of food. However, it is much more fascinating to know that each of our cells is coated in sugar molecules, like candied apples at Christmas markets. When two cells interact with each other, this usually happens via the sugar molecules on their surfaces, much like candied apples would stick together if they came into contact. Monosaccharides are the fundamental building blocks of sugar molecules. Even the space between our cells consists to a large degree of long sugar chains that provide the tissues with the necessary stability and structure – think of it like several candied apples in a mountain of cotton candy. Our cells’ surfaces are so sugary because they consist of proteins that are often coated in special sugar molecules known as N-glycans. These are rather small molecules that consist of 10 to 20 different monosaccharides, whose structure resembles a tree with one trunk (parent chain) from which many ramified branches extend. The end of the parent chain, where the roots would descend from the base of a tree trunk, is connected to the protein and the ascending branches swing back and forth like a tree in the wind. Picture a young willow with flexible young branches, not a gnarled oak.

Altered Sugar Molecules Signal Disease

There is a bitter aftertaste to this sugary notion of ours, however, because if anomalies arise in the sugar chains on our cells, as observed in alterations to the color or structure of the sugarcoating, this is often a sign of disease or infection. For example, we know that the tumor cells of breast, intestinal, and skin cancer are coated in more strongly branched sugar molecules whose cell surface structure differs from that of the body’s healthy cells. This difference alters how cells interact with the rest of the tissue and encourages metastasis.

Such modifications in the sugarcoating are caused by the cell itself, because all N-glycan production takes place in a multi-step process within the cell or with the help of special enzymes that either bind or separate monosaccharides. Changes in cellular metabolism can result in an overabundance of a certain enzyme, for example alpha-mannosidase-2, and this in turn causes a change in the pattern of the sugarcoating, as is the case in tumor cells. Restoring a balance with “healthy” N-glycan structures requires inhibiting the problematic enzyme. Among other methods, this balance can be obtained using medication that binds to the enzyme in question and prevents the N-glycans from binding. Developing a medication with this capability is easier said than done, since preventing unwanted side effects requires being able to form a bond successfully and permanently with only this specific enzyme. Doing so requires knowing not only the structure of the enzyme but also that of the N-glycan after it is bound, since enzymes are very selective and can only bind to specific 3D structures, similar to a lock for which only one key fits.

Computer Simulations Can Predict Sugar Structures

This presents quite the challenge, because like a tree moving in the wind, an N-glycan not only takes on a 3D structure, its flexibility also causes it to alternate between different forms. This structural variability is difficult to determine in lab experiments that only produce a blurred image, similar to photographing a tree in a storm with a two-minute exposure time. What would be required would be a time lapse recording of every single movement of each branch.

Computer simulations provide this capability, working like a film that depicts each atom explicitly and lets us observe the movement of a sugar molecule over time. At the same time, the structure of the N-glycan is repeatedly determined at certain time intervals by calculating the angles between the individual monosaccharides within the sugar tree. These simulations often result in a stack of over 10,000 photos that need to be sorted. Our Hybrid Materials Interfaces research group has developed a new method for classifying and grouping the different sugar tree structures in the individual photos based on the measured angles. This provided us with the possibility to make quantitative assessments about which 3D structures an N-glycan named M5G0 assumes and which interactions it has with the enzyme alpha-mannosidase 2. These are groundbreaking medical discoveries about the significance of sugar structure flexibility and may contribute to the development of a cancer medication in the future.

Glycobiology – An Underestimated Research Field with Medical Potential

Being able to analyze the movements of sugar molecules at a microscopic level provides insight into many other processes within our body. Our cells’ sugarcoating can also be changed by invasive parasites, leading to diseases such as sleeping sickness, which is widespread on the African continent. The bite of a tsetse fly transmits single-celled parasites into our bloodstream. The surface of these parasites harbors the enzyme trans-sialidase, which makes its way to the sugarcoating of our red blood cells and eats away at certain monosaccharides. The resulting structural change ultimately leads to symptoms such as anemia and, depending on the type of infection, can be deadly. We were able to show that the flexibility of the N-glycans present on the surface of the trans-sialidase plays an important role here as well, since it influences the enzyme’s activity which is directly connected to the infectivity and symptoms of the sleeping sickness. Removing the regulating N-glycans led to a reduced activity of the trans-sialidase in lab experiments, a mechanism that could be a breakthrough in combating sleeping sickness.

Despite its long history, the field of glycobiology seems to still be in its infancy, and is relatively unknown. However, recent developments are particularly promising, especially those regarding bioorthogonal chemistry by Carolyn Bertozzi, who was awarded the chemistry Nobel prize in 2022. She showed that N-glycans in cell surfaces can be specifically marked, thereby providing a possibility to target a medication’s effects in the body in the future. While we continue to work on uncovering the mysterious workings of sugar in our body, we can reassure ourselves that we are doing something good by our cells by ingesting sugar as we reach for the next chocolate bar. We’re just keeping our cells’ sugarcoating intact and healthy, and conclude that the old adage “moderation in all things” remains true.

This article comes from MINTScience Blog

The MINTScience Blog (“MINT” is the German term for “STEM”) from the University of Bremen explains complex research topics to a broad audience. Students and early-career researchers wish to use the blog to clearly explain difficult issues.