By Isabell Grothaus

Figure 1 – Source: Dall-E.

Sugar is not only converted into energy in our body, it also protects us from diseases and infections. This is because nearly all of our cells are coated with a dense sugar glaze. However, if parasites start nibbling on these sugars, it can become dangerous for us.

Sweet temptation lurks everywhere: in the morning, sugar hides in the jam at breakfast, and in the evening, it tempts us in the form of chocolate. Who doesn’t know the feeling? By the end of the day, we regret succumbing to these sweet temptations. After all, one thing is clear: sugar is considered unhealthy.

But what about the potatoes at lunch? Hardly anyone considers that. From a chemical perspective, they consist of about 73% carbohydrates—essentially sugar. The majority of this is glucose, the same monosaccharide found in table sugar. This raises the question: “Why don’t potatoes taste sweet, even though they contain so much sugar?”

The subtle yet crucial difference lies in how monosaccharides, the fundamental building blocks of sugar molecules, are linked together. Short forms like lactose consist of a few linearly connected monosaccharides and taste sweet. In contrast, starch, which makes up the majority of sugar in a potato, is a highly branched molecule composed of well over 1,000 glucose units. Receptors on our tongue can detect shorter sugar molecules much better than larger ones, triggering the ‘sweet’ signal in our brain.

One might think that sugar plays a role in our lives only as food. But what’s even more fascinating is that every one of our cells is coated with sugar molecules, like candied apples at a Christmas market. And when two cells interact, they often do so through the sugar molecules on their surfaces, just as candied apples would stick together if they touched. Even the space between our cells largely consists of long sugar chains, which provide the tissue with necessary stability and structure. Imagine a lot of candy apples in a mountain made of cotton candy.

Our cell surfaces are so well-sugared because the proteins within them are often coated with special sugar molecules called N-glycans. These are relatively small molecules, consisting of 10 to 20 different monosaccharides, structured like a tree with a trunk and several branching limbs. The end of the trunk, where the roots of the tree begin, is connected to the protein and the branches sway back and forth like a tree in the wind. Imagine a willow tree with flexible young branches, rather than a gnarled oak.

This sugary sweet image, however, has a bitter aftertaste, because when anomalies occur in the sugar chains on our cells, such as changes in the color or structure of the sugar coating, it is often a sign of disease or infection. For example, it is known that tumor cells in breast, colon, or skin cancer have more branched sugar molecules with a different structure on their cell surface compared to healthy body cells. This difference leads to altered interactions with the surrounding tissue and promotes the spread of metastases.

Changes in the sugar coating are triggered by the cell itself, as it produces all N-glycans step by step inside the cell with the help of special enzymes that either link or separate monosaccharides. If a particular enzyme, such as alpha-mannosidase 2, becomes too abundant in the cell due to metabolic changes, it leads to a change in the pattern of the sugar coating, as seen in tumor cells. In order to restore the balance with ‘healthy’ N-glycan structures, the problematic enzyme must be inhibited. This can be done, among other methods, with medications that bind to the enzyme and prevent the binding of the actual N-glycan. This is easier said than done, as ensuring that a medication successfully and permanently binds to only this one enzyme — without causing side effects — is a major challenge. One must first understand both the structure of the enzyme and the structure of the N-glycan when it is bound, because enzymes are very selective and can only bind specific 3D structures, much like a lock that only fits one key.

And that’s exactly the challenge. Like a tree in the wind, an N-glycan can not only adopt a 3D structure, but it can also switch back and forth between different forms due to its flexibility. This structural variability is difficult to determine in laboratory experiments, often resulting in a blurry image, as if you were photographing a tree during a storm with a two-minute exposure. What is needed, however, would be a time-lapse recording of every single oscillation of each branch.

The solution to this problem lies in computer simulations. They work like a movie, where each atom is explicitly represented, and the movements of the sugar molecules can be observed over time. The structure of the N-glycan is determined by calculating the angles between the individual monosaccharides in the sugar tree. These simulations often result in a stack of over 10,000 photos that need to be sorted. We’ve developed a new method to classify and group the different sugar tree structures in each photo, based on the measured angles. This allowed us to make quantitative statements about which 3D structures an N-glycan called M5G0 adopts and how it interacts with the enzyme alpha-mannosidase 2. These groundbreaking insights into the significance of sugar structure flexibility in medicine could contribute to the development of a drug against cancer in the future.

Being able to analyze the movements of sugar molecules on a microscopic level provides insight into many other processes in our body. The sugar coating on our cells can be altered by invading parasites, leading to diseases such as sleeping sickness, which is widespread across the African continent. Single-celled parasites enter our bloodstream through the bites of the tsetse fly. They carry the enzyme trans-sialidase on their surface, which interacts with the sugar coating on our red blood cells and removes specific monosaccharides.The resulting structural change ultimately leads to symptoms such as anemia and, depending on the type of infection, can even be fatal. We were able to show that the flexibility of the N-glycans on the surface of the trans-sialidase plays a crucial role here, as it affects the enzyme’s activity, which is directly related to the infectivity and symptoms of sleeping sickness. Removal of the regulating N-glycan has led to reduced activity of trans-sialidase in lab experiments, a mechanism that could be groundbreaking in the fight against sleeping sickness.

The field of glycobiology is still in its infancy and relatively unknown, but the development of ‘bioorthogonal chemistry’ by Carolyn Bertozzi, winner of the 2022 Nobel Prize in Chemistry, gives hope. She’s demonstrated that N-glycans on cell surfaces can be specifically labeled, making it possible for drugs to be targeted within the body in the future. As long as we continue to work on deciphering the secrets of sugar in our bodies, we can at least justify our next piece of chocolate by the fact that the sugar we consume does something good for our cells. We just have to make sure that the sugar coating maintains a healthy structure. So in the end, unfortunately, it still means: Everything in moderation.