Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.

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Biological Roles of Glycans

The Symbol Nomenclature for Glycans (SNFG) is a community-curated standard for the depiction of monosaccharides and complex glycans using various colored-coded, geometric shapes, along with defined text additions. It is hosted by the National Center for Biotechnology Information (NCBI) at the NCBI-Glycans Page (www.ncbi.nlm.nih.gov/glycans/snfg.html). Several changes have been made to the SNFG page in the past year to update the rules for depicting glycans using the SNFG, to include more examples of use, particularly for non-mammalian organisms, and to provide guidelines for the depiction of ambiguous glycan structures. This Glycoforum article summarizes these recent changes.

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Updates to the Symbol Nomenclature for Glycans guidelines.

Small RNAs are modified with N-glycans and displayed on the surface of living cells.

Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan modification pathways. The vast majority of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly growth failure, developmental delay, facial dysmorphisms, and variable coagulation and endocrine abnormalities. Carbohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis. Early detection is important, as a few of these disorders are treatable. Molecular and biochemical techniques continue

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Congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are one group among the disorders of glycosylation. The latter comprise defects associated with hypoglycosylation but also defects with hyperglycosylation. Genetic diseases with hypoglycosylation can be divided in primary congenital disorders of glycosylation (CDG) and in genetic diseases causing secondary hypoglycosylation. This review covers the human CDG highlights from the last 3 years (2014-2016) following a summary of the actual status of CDG. It expands on 23 novel CDG namely defects in SLC39A8, CAD, NANS, PGM3, SSR4, POGLUT1, NUS1, GANAB, PIGY, PIGW, PIGC, PIGG, PGAP1, PGAP3, VPS13B, CCDC115, TMEM199, ATP6AP1, ATP6V1A, ATP6V1E1, TRAPPC11, XYLT1 and XYLT2. Besides, it discusses novel phenotypes of known CDG (DHDDS-CDG, ALG9-CDG, EXT2-CDG, PIGA-CDG, PIGN-CDG), the elucidation of putative glycosyltransferase disorders as O-mannosylglycan synthesis disorders (TMEM5-CDG, ISPD-CDG, FKTN-CDG, FKRP-CDG), a novel CDG mechanism, advances in diagnosis, pathogenesis, treatment and finally an updated list of the 104 known CDG.

https://onlinelibrary.wiley.com/doi/pdf/10.1007/s10545-017-0050-6

What is new in CDG

Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy

The Muscular Dystrophy Gene TMEM5 Encodes a Ribitol β1,4-Xylosyltransferase Required for the Functional Glycosylation of Dystroglycan.

Tn-antigens are tumour-associated carbohydrate antigens that are involved in metastatic processes and are associated with a poor prognosis. MLS128 monoclonal antibody recognizes the structures of two or three consecutive Tn-antigens (Tn2 or Tn3). Since MLS128 treatment inhibits colon and breast cancer cell growth [Morita, N., Yajima, Y., Asanuma, H., Nakada, H., and Fujita-Yamaguchi, Y. (2009) Inhibition of cancer cell growth by anti-Tn monoclonal antibody MLS128. Biosci. Trends 3, 32-37.], understanding the interaction between MLS128 and Tn-clusters may allow us to the development of novel cancer therapeutics. Although MLS128 was previously reported to have specificity for Tn3 rather than Tn2, similar levels of Tn2/Tn3 binding were unexpectedly observed at 37°C. Thus, thermodynamic analyses were performed via surface plasmon resonance (SPR) using synthetic Tn2- and Tn3-peptides at 10, 15, 20, 25 and 30°C. SPR results revealed that MLS128's association constants for both antigens were highly temperature dependent. Below 25°C MLS128's association constant for Tn3-peptide was clearly higher than that for Tn2-peptide. At 30°C, however, the association constant for Tn2-peptide was higher than that for Tn3-peptide. This reversal of affinity is due to the sharp increase in K(d) for Tn3. These results were confirmed by NMR, which directly measured MLS128-Tn binding in solution. This study suggested that thermodynamic control plays a critical role in the interaction between MLS128/Tn2 and MLS128/Tn3.

Hiroko Kawakami

Papers

Identification of a Post-translational Modification with Ribitol-Phosphate and Its Defect in Muscular Dystrophy

The Muscular Dystrophy Gene TMEM5 Encodes a Ribitol β1,4-Xylosyltransferase Required for the Functional Glycosylation of Dystroglycan.

Surface plasmon resonance and NMR analyses of anti Tn-antigen MLS128 monoclonal antibody binding to two or three consecutive Tn-antigen clusters.