*Editorial* **Preface for the Special Issue on the Exploration of the Multifaceted Roles of Glycosaminoglycans: GAGs**

**Dragana Nikitovic 1,\* and Serge Pérez <sup>2</sup>**


Glycosaminoglycans (GAGs) are linear, anionic polysaccharides that consist of repeating disaccharides of hexosamine and hexuronic acid. The exception to this is keratan sulfate, whose building blocks consist of hexosamine and galactose. Differences in the primary disaccharide unit structure regarding uronic acid and hexosamine, the number and position of the sulfate residues, the presence of *N*-acetyl and/or *N*-sulfate groups, and the relative molecular mass are evident. All such differences bestow these biomolecules with impressive complexity and diversity. The fine structure of the disaccharide units defines the types of GAGs. These include chondroitin/dermatan sulfate (CS/DS), heparin/heparan sulfate (Hep/HS), and keratan sulfate (KS), as well as non-sulfated hyaluronan (HA) (Figure 1).

GAGs are ubiquitously localized throughout the extracellular matrix (ECM) and to the cell membranes of cells in all tissues. They are either conjugated to protein cores in the form of proteoglycans, e.g., CS/DS, HS, and KS, or as free GAGs (HA and Hep). Through their interaction with proteins, GAGs can affect the cell-extracellular matrix (ECM) and cell–cell interactions, finely modulating ligand-receptor binding and thus chemokine and cytokine activities as well as growth factor sequestration. Thus, GAGs regulate several biological processes under homeostasis; they also participate in disease progression. Recently, significant advances have been made in the analytic, sequencing, and structural characterization of GAG oligosaccharides as well as in GAG profiling in tissues and cells (GAGomics). Moreover, studies focused on the structure/sequence-function relationships of GAGs have resulted in critical novel insights. Furthermore, advances in the characterization of protein–GAG complexes provide invaluable tools to decipher GAG's roles in the intricate tissue milieu and answer critical questions regarding GAG participation in the molecular basis of disease and embryonic development.

This Special Issue of *Biomolecules*, entitled "Exploring the multifaceted roles of glycosaminoglycans (GAGs)—new advances and further challenges", features original research and review articles. These articles cover several timely topics in structural biology and imaging; morphogenesis, cancer, and other disease therapy and drug developments; tissue engineering; and metabolic engineering. This Special Issue also includes an article illustrating how metabolic engineering can be used to create the novel chondroitin-like polysaccharide.

A prerequisite for communicating in any discipline and across disciplines is familiarity with the appropriate terminology. Several nomenclature rules exist in the field of biochemistry. The historical description of GAGs follows IUPAC and IUB nomenclature. New structural depictions such as the structural nomenclature for glycan [1] and their translation into machine-readable formats [2,3] have opened the route for cross-references with popular bioinformatics resources and further connections with other "omics".

**Citation:** Nikitovic, D.; Pérez, S. Preface for the Special Issue on the Exploration of the Multifaceted Roles of Glycosaminoglycans: GAGs. *Biomolecules* **2021**, *11*, 1630. https:// doi.org/10.3390/biom11111630

Received: 22 October 2021 Accepted: 26 October 2021 Published: 4 November 2021

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**Figure 1.** Cartoon representation of the chemical constitution of the five families of GAGs and of six categories of proteoglycans (aggrecan; decorin, perlecan, and collagen; glypican; and syndecan and serglycin). ES, extracellular; IS, intracellular; N, nucleus; SV, secretory vesicle. (Adapted from K. Rodgers, J.D. San Antonio, O. Jacenko. Dev Dyn. 2008, 237, 2622–2642).
