Specific sides to multifaceted glycosaminoglycans are observed in embryonic development

Abstract

Ubiquitously found in the extracellular matrix and attached to the surface of most cells, glycosaminoglycans (GAGs) mediate many intercellular interactions. Originally described in 1889 as the primary carbohydrate in cartilage and then in 1916 as a coagulation inhibitor from liver, various GAGs have since been identified as key regulators of normal physiology. GAGs are critical mediators of differentiation, migration, tissue morphogenesis, and organogenesis during embryonic development. While GAGs are simple polysaccharide chains, many GAGs acquire a considerable degree of complexity by extensive modifications involving sulfation and epimerization. Embryos that lack specific GAG modifying enzymes have distinct developmental defects, illuminating the importance of GAG complexity. Revealing how these complex molecules specifically function in the embryo has often required additional approaches, the results of which suggest that GAG modifications might instructively mediate embryonic development.

Figure 1. Interrelated biosynthesis of GAG classes yields similar yet distinct structures

(A) GAGs are classified based on their disaccharide building blocks. Potentially modified positions are highlighted in red. (B) Numerous enzymes catalyze GAG elongation and modification. Families of enzymes involved in each step are listed with the number of homologs from humans-H compared to four models organisms: mouse-M, zebrafish-Z, Drosophila -D, and C elegans-E. Saccharides that link KS to core proteins are quite diverse and simplified here for clarity. Descriptions of each gene family along with specific gene IDs are in the Supplemental. (C) GAGs adopt distinct helical conformations. Illustrations were generated using Chem3D Pro with the pdb files 2BVK (HA), 2KQO (CS), and 1HPN (Heparin). *Saccharides and modifications are abbreviated using the following nomenclature: GluA, β-D-glucuronic acid; GlcNAc, α/β-D-glucosamine; GalNAc, β-D-galactosamine; Gal, β-D-galactose IdoA, α-L-iduronic acid; NAc, N-acetylation; SO₄⁻, sulfate. Specific disaccharides are condensed. For example, the disaccharide containing glucuronic acid linked to a 4-O and 6-O sulfated galactosamine is represented by GlcA-GalNAc4S, 6S.