Introduction to a special issue, “Expanded glycomics: A bridge over future glycomics”

Glycans form an important class of biopolymers comparable to nucleic acids (DNA and RNA) and proteins [1]. However, glycans exhibit extremely heterogenous features which other biopolymers lack, e.g., branching and further post-glycosylation modifications. With such obvious obstacles, glycan functions remain largely unknown. Nevertheless, recent progress in separation and analytical sciences made it possible to investigate glycopeptides for a diagnostic purpose [[2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]].

Glycosylation pathway in higher vertebrates requires a large panel of enzymes with various subcellular localizations. Thus, it comes as no surprise that any deregulation of glycans synthesis, trafficking, turn-over or localization may induce variable clinical effects. Thus, the combination of dynamic and precise monitoring of differentiated glycans expression with new molecular sensor devices creates a wealth of opportunities for the early diagnosis of metabolic, inflammatory, genetic and infectious diseases, offering patients personalised treatment regimens. In the present issue, we introduce a number of glycomics and glycoproteomics initiatives focuses on new biomarker development (Part 1: MS-based glycomics/glycoproteomics and clinical applications; in this special issue see [[15], [16], [17], [18]]). In view of the extensive structural heterogeneity of glycosylation, there is an imperative need for novel tools to facilitate the exploration and development of methodologies that will reveal additional structural aspects in both human and non-human models. In addition to the high-throughput analyses of glycosylation facilitated by the development of mass spectrometry-based glycomics and glycoproteomics methods that enable cohort studies to be conducted, it is also essential to be able to discriminate non-canonical and/or unexpected glycan epitopes. We present several projects combining MS, LC/MS, sensors and chemical methods to generate more efficient and in-depth glycomic mapping in discovery mode. (Part 2: Advanced technologies for glycomics/glycoproteomics; see [[19], [20], [21], [22], [23], [24], [25], [26], [27], [28]]).

The biosynthesis of glycoconjugates (i.e. the sugar and its protein/lipid moiety) requires the coordinated activity of a series of enzymes (including glycosyltransferases, epimerases, sugar transporters, etc.) that operate without a genetic template and are capable of creating the myriad structures that fulfil a variety of essential functions. Systematic studies of glycoconjugates in many animal phyla have revealed two important facts. Firstly, the structural diversity of glycans is limitless, thus rendering them the most heterogeneous polymers in nature and conferring an enormous coding capacity for the transfer of biospecific information beyond the genetic code. Secondly, the structure of glycans appears to be species-specific. Although some glycans are ubiquitous in the animal kingdom, it is believed that each animal species has strictly specific glycosylation patterns, resulting from the extreme susceptibility of all biosynthetic actors to change and mutation. Despite the significant recognition of glycoconjugates as key players in various biological processes, the scientific community still lacks a comprehensive understanding of the diversity of glycans and their biosynthetic pathways across all branches of life, including in animals. From a fundamental point of view, this appears as a major shortcoming not only to the study of glycoconjugate specific functions, but also to the understanding of the molecular bases and the evolution of many primordial biological processes in which glycoconjugates are key elements. Here are presented a number of studies that extend structural analyses to many organisms, including microorganisms, of great scientific value (Part 3a: Comparative glycomics; see [[29], [30], [31], [32], [33]]). As glycans are the most structurally diverse and rapidly evolving major class of molecules, a large variety of lectins have evolved to recognize this diversity, reflecting both endogenous (such as the need for cell-cell communication and signaling within an organism) and exogenous (such as pathogen recognition and defense) selection pressures [34]. This is evident in the large variety of lectins found across all domains of life, each adapted to bind specific glycan structures. In this context, we present several studies that recapitulate and extend our knowledges on lectins from both vertebrates and invertebrates (Part 3b: Comparative lectinomics; see [[35], [36], [37], [38], [39]]).

While only a handful are common in humans and other vertebrates, several hundreds of different monosaccharides have been identified in nature, with the actual number likely much higher, especially considering the diversity found in microbes [40]. Despite this staggering structural and biological diversity one may question the usefulness of rare and unnatural sugars for a number of applications and ask “What happens if non-natural sugars become available in our hands?” Hence, we plot an independent section related to non-natural glycans in particular at the monosaccharide level (Part 4: Non-natural glycome; see [41,42]). Lastly, those data above described are integrated by informatics in terms of public databases and further to develop analytical tools to predict complex glycan biosynthesis (Part 5: Systems biology/databases; see [43,44]).

Taken together all these glycomics-related issues will be consistently understood under the new concept of “Expanded Glycomics”, a theme of this special issue.