**2. Focus on GAGs' Structure and Roles**

GAG polymers are assembled through several consecutive steps with different enzymes' involvement at each separate stage. Sulfated GAGs are synthesized by specific enzymes in the cell's Golgi apparatus, whereas HA is synthesized by transmembrane proteins called HA synthases (HASs). While HA is not linked to a protein and is produced from its reducing end, the sulfated GAGs are built up from the non-reducing end and synthesized as side chains attached to a protein core of PGs [5].

In the case of KS, GlcA is replaced by GalN. Henceforth, the growing GAG chain's modifications, e.g., deacetylation/N-sulfation and epimerization of GlcA to IdoA followed by O-sulfation, are performed [30,31]. Therefore, the individualized functionalization of GAGs results in their unique structures. Indeed, distinct sulfation patterns have been identified at the disaccharide unit's functionalization sites, hexosamine, and IdoA components, facilitating great complexity and structural diversity [32,33].

Different variations in the expressions/activities of enzymes involved in GAG synthesis have been described. One example is that the levels of exostoses (multiple)-like 1 (EXTL1) and CS N-acetylgalactosaminyltransferase 1 (CSGalNAcT-1), which participate in the production of HS and CS, respectively, were shown to exhibit an inverse ratio of expression. The inverse expressions identified in the process of B-cell differentiation have been suggested to act as a switch enabling either CS or HS synthesis observed during these cell differentiations [34].
