Selective modification of substrate by GnT-V in polarized kidney tissue in mice. Credit: iScience (2025). DOI: 10.1016/j.isci.2025.113894

Glycans are important complex carbohydrates found on cell surfaces that serve crucial roles in cell-to-cell communication, structure, and protection. They are attached to many proteins in the body, and their attachment differs protein to protein. Researchers have aimed to investigate the selectivity of a specific, cancer-related enzyme, N-acetylglucosaminyltransferase-V (GnT-V or MGAT5).

GnT-V is often abnormally upregulated and can be an indicator of a poor prognosis in cancer diagnoses, with N-glycans individually associated with diseases such as Alzheimer’s, emphysema, diabetes and cancer. Understanding why and how GnT-V selects substrates may offer therapeutic solutions for diseases involving this enzyme.

The glycosylation process of proteins is a common and regular modification after they have been synthesized, and is the addition of carbohydrates to the protein. There are two classes, N-glycosylation and O-glycosylation, but N-glycosylation is the primary target of the study.

“Glycans are attached to tons of proteins, and we all know that glycan structures slightly differ protein to protein. This means that glycan biosynthetic enzymes somehow select their substrate proteins, but it’s totally unclear how this happens,” said Kizuka Yasuhiko, professor at Gifu University and author of the study published in iScience.

The study revealed the selective preference for GnT-V based on two factors: the three-dimensional structure of the protein and subcellular trafficking (the movement of molecules within a cell) in polarized cells. Polarized cells have two distinct parts, separated by an axis, each is responsible for different roles and is composed differently.

The parts are often referred to as basal (bottom) and apical (top). However, with this study taking place in mice and mouse kidney tissue, it is unclear whether the selectivity as it relates to polarity can be extrapolated to other organ tissues.

Two enzymes specializing in the breakdown of proteins with metal ions attached (metalloproteases) were identified as the major substrates of GnT-V in the kidney, localizing mostly at the apical surface. The selection of these substrates seems to rely mostly on the trafficking in the apical part of the cell along with its structure, so further clarification on how exactly GnT-V selects the substrates is necessary to make full use of the knowledge gleaned from this study.

Along with the necessary future investigation, there are some limitations to this study: the reliance on a certain protein to identify the glycoprotein substrates of GnT-V leaves room for the potential that some glycoproteins are overlooked. Additionally, polarized cells (cells with two distinct surfaces) are used in this study, and it isn’t fully known whether GnT-V modification depends on cell polarity.

Despite limitations, researchers would like to continue the study to fully understand the mechanism of how glycan structures are shaped for each glycoprotein.

“This could lead to the precise prediction of glycan structures of each glycoprotein in cells, contributing to eventual remodeling of glycans for therapeutic purposes,” said Yasuhiko.

More information: Reina F. Osuka et al, Selective modification of glycoprotein substrates by GnT-V in mouse kidney, iScience (2025). DOI: 10.1016/j.isci.2025.113894

Provided by Institute for Glyco-core Research (iGCORE)

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