An intramolecular energy metabolism fueling the chain elongation-translocation cycle in hyaluronic acid synthesis

Inside the microscopic world of living cells, a constant, quiet construction project is underway. Cells build long, chain-like molecules called polysaccharides, which act as the structural scaffolding and signaling networks for life. These chains, made of repeating sugar units, are essential for everything from the elasticity of our skin to the protective capsules surrounding certain bacteria. A critical factor in how these molecules function is their length. Just as a short rope cannot perform the same task as a long one, the size of these sugar chains determines whether they calm inflammation or trigger it, or whether they help a tissue heal or allow a tumor to grow. The machines responsible for building these chains, known as synthases, must not only link the sugar pieces together but also push the growing chain out of the factory floor and into the cell's outer environment. For decades, scientists have understood how these machines grab the raw materials and snap them together, but the mechanism that powers the physical movement of the chain—how the machine pushes the growing rope through a narrow tunnel in the cell membrane—has remained a mystery.

A team of researchers at Tsinghua University has now illuminated this hidden process, revealing that the machine itself generates the energy needed to push the chain forward. They focused on the enzyme that builds hyaluronic acid, a vital sugar chain found in human connective tissues and the capsules of certain bacteria. Using a combination of advanced computer simulations and laboratory experiments, the scientists discovered that the enzyme does not rely on a separate fuel source to move the chain. Instead, it harvests energy from the very chemical reaction that builds the chain. When the enzyme attaches a new sugar unit, it releases a small chemical byproduct. The researchers found that the breaking apart of this byproduct triggers a shape change in the enzyme, which acts like a mechanical lever to shove the growing chain forward through a tunnel in the cell membrane.

The study began by observing the enzyme in a simulated environment, watching how the chain behaved after a new sugar unit was added. The simulations showed that without any extra push, the chain would simply wiggle in place, unable to move far enough to make room for the next piece. The chain was effectively stuck, held in place by the leftover chemical byproduct. The researchers realized that for the chain to move, this byproduct had to be removed. They observed that once the byproduct was broken down, the chain spontaneously shifted forward by a tiny fraction of a nanometer. This small movement was the key. It unlocked a larger mechanism where the enzyme's internal tunnel, which had been a smooth cylinder, suddenly constricted in the middle to form an hourglass shape. This constriction grabbed the chain, twisted it slightly, and pulled it further out, clearing the path for the next round of construction.

To confirm this mechanism, the researchers looked for a way to provide extra energy to the system, hypothesizing that if the chain was stuck due to a lack of energy, adding a universal cellular fuel might help. They introduced adenosine triphosphate, or ATP, a molecule cells use to store energy, into their test tubes containing the enzyme. They found that adding a specific amount of ATP allowed the enzyme to build much longer chains than usual. The enzyme was capable of breaking down this ATP and using the released energy to power the movement of the chain, effectively giving the machine a second wind. This discovery was significant because it showed the enzyme could switch between using the energy from its own building blocks and using external energy, depending on the conditions. The researchers identified two distinct spots on the enzyme where this energy-breaking could happen: one at the main construction site and another on the enzyme's surface, allowing it to adapt to different energy levels in the cell.

The implications of this finding extend far beyond hyaluronic acid. The researchers tested their theory against other types of sugar-chain building machines, including those that make cellulose in plants and chitin in insect shells. Their analysis suggested that this method of using internal chemical energy to drive physical movement is a universal strategy used by nature to build these long, complex molecules. The study suggests that the size of these chains is not just a matter of how many pieces are added, but a balance between the energy available to push the chain out and the resistance the chain faces as it grows. If the resistance becomes too high, the chain stops growing. If the enzyme can access extra energy, like the ATP they introduced, it can overcome that resistance and build longer, more functional chains.

This work provides a new understanding of how cells manage the physical work of building their own structures. It reveals that the process is not a passive assembly line but a dynamic, energy-harvesting cycle where the act of building is inextricably linked to the act of moving. By uncovering the specific steps where the enzyme changes shape and uses chemical energy to perform mechanical work, the researchers have opened a window into the fundamental mechanics of life. This knowledge could eventually help scientists design better ways to produce these molecules for medical use or understand how diseases arise when this delicate energy balance is disrupted. The study confirms that the machinery of life is not just a static blueprint but a self-fueling engine, constantly converting chemical signals into the physical motion required to sustain the complex structures of living organisms.