Brain enzyme caught doing something unexpected—it builds polysialic acid on itself

The three enzymes shown here build polysialic acid (orange), a long sugar chain important for brain development and function. ST8Sia5L (left) builds the chain only on itself, a newly discovered activity. ST8Sia2 (center) and ST8Sia4 (right) build it on other molecules. Credit: Sakamoto et al., 2026

A chance discovery at Nagoya University in Japan has shown that a well-known brain enzyme has a hidden ability: It builds a sugar chain on itself, becomes secreted from the cell and deactivates, then switches on outside the cell once the chain is removed. The finding, published in the Journal of Biological Chemistry , overturns a decades-old assumption about how polysialic acid, a sugar chain critical for brain development and function, is produced and shows a new way an enzyme can regulate its own activity.

The brain's sugar chains

The human brain is covered in sugar chains, or glycans, molecular structures that coat cells and regulate how they communicate. One of the most important is polysialic acid, a long chain found mainly in the brain.

Polysialic acid keeps brain cells from adhering too tightly to each other and binds to growth factors and neurotrophins to regulate the presentation of their receptors. Through this, it plays a key role in learning, memory and neural development. Importantly, these sugar chains change rapidly in response to brain activity. The ability to restore them quickly is thought to be essential for normal brain function.

Until now, scientists believed only two enzymes were responsible for building polysialic acid in the brain: ST8Sia2 and ST8Sia4.

The three enzymes shown here build polysialic acid (orange), a long sugar chain important for brain development and function. ST8Sia5L (left) builds the chain only on itself, a newly discovered activity. The four labeled amino acids on ST8Sia5L (R289, R333, and K380 in red; Y286 in green) are important for its polysialic acid synthesis. The resulting polysialic acid silences enzyme activity and triggers its secretion from the cell. ST8Sia2 (center) and ST8Sia4 (right) mainly add polysialic acid to other molecules. Credit: Sakamoto et al., 2026

A chance discovery

ST8Sia5 was discovered in 1996 and was known only as a builder of fatty brain molecules called gangliosides. Its ability to produce polysialic acid was unknown until now.

The enzyme exists in three forms, short (S), medium (M) and long (L), that differ only in the length of one structural region. Only the long form, ST8Sia5L, showed this newly discovered activity. Unlike the short and medium forms, ST8Sia5L localizes to a different intracellular compartment, which may allow it to undergo autopolysialylation. The function of the short and medium forms is not yet known.

Nagoya University's Institute for Glyco-core Research (iGCORE) had been testing all six members of the ST8Sia enzyme family.

"We found that a third enzyme, ST8Sia5, also builds polysialic acid, but only on itself, and only in its longest form, ST8Sia5L," said first author Fumiya Sakamoto.

Co-author and Director of iGCORE Chihiro Sato said, "We were checking each enzyme one by one and found this activity by chance."

Four discoveries that define this mechanism:

1. The enzyme builds its own off switch. Unlike most enzyme regulation, where a separate molecule switches an enzyme on or off, ST8Sia5L modifies itself. It builds polysialic acid chains directly onto its own structure, a process called autopolysialylation. No external regulator is required.

2. The sugar chain is the switch. Polysialic acid is not typically known as a regulator of enzyme activity, but here it acts as one. While the chain is attached, the enzyme's ganglioside-building function is completely suppressed. This is a new role for polysialic acid.

3. Self-modification is linked to secretion. Once coated in polysialic acid, the enzyme is cut free from the cell membrane by metalloprotease enzymes and released into the fluid outside the cell. The sugar coat does not just silence the enzyme; it is also associated with its release from the cell.

4. The enzyme reactivates outside the cell. The researchers showed experimentally that the secreted enzyme, collected from outside the cell, regains its ganglioside-building activity once the polysialic acid chains are removed. This could happen, for example, when sialidase enzymes are released during stress or inflammation. Reactivation does not require the enzyme to re-enter the cell.

A surprise finding for other enzymes too

The ST8Sia family are all sialic acid-building enzymes, but they differ in how long a chain they build. Most add just two or three units. ST8Sia2 and ST8Sia4 were the only ones known to build long chains of polysialic acid. ST8Sia5L has now joined that group, but with one key difference: It only builds the long chain on itself, not on other molecules.

The study also found, for the first time, that ST8Sia2 and ST8Sia4 are secreted from cells in a polysialic acid-coated form. Wh…