Biological roles of glycans

Abstract

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.

Keywords: biological roles; evolution; glycans.

Fig. 1.

Universal characteristics of all living cells. As indicated in the figure and discussed in the text, glycosylation is among the key features of all living cells. However, in contrast to the genetic code, the degree of chemical complexity and evolutionary diversification of glycans amongst various taxa is the greatest. The likely reasons for this difference are discussed in the text, and can help explain the still rather limited knowledge base regarding this class of molecules. But we now know that dense and complex glycosylation is universal to all living cells and even most viruses. Evidently, more than 3 billion years of evolution has failed to generate a free-living cell devoid of glycosylation. Thus, one can conclude that glycosylation is as essential to life as a genetic code. Figure modified from ref. and used with permission from Varki A. 2011a. Cold Spring Harb Perspect Biol. 3, doi:pii: 10.1101/cshperspect. a005462. Copyright: Cold Spring Harbor Laboratory Press.

Fig. 2.

Accelerating progress in the discovery of human glycosylation disorders. The graph shows the cumulative number of human disorders with a major genetic defect in various glycosylation pathways and the year of their identification (2016 data for first 6 months). In early years, initial discovery was based on compelling biochemical evidence, and in later years by conclusive genetic proof. In most instances, the year indicates the occurrence of definitive proof of gene-specific mutations and correlations to biochemical results. Figure kindly provided by H. Freeze and Bobby Ng, updated from ref. and reproduced with permission from Freeze HH, Chong JX, Bamshad MJ, Ng BG. 2014. Am J Hum Genet. 94:161–175. Copyright Elsevier. Reproduced with permission.

Fig. 3.

General classification of the biological roles of glycans. A simplified and broad classification is presented, especially emphasizing the roles of organism-intrinsic and organism-extrinsic glycan-binding proteins in recognizing glycans. There is some overlap between the categories, e.g., some structural properties involve specific recognition of glycans. Binding shown on the left of the central “self” cell represents intrinsic recognition, and extrinsic recognition is represented by binding shown to the right of that cell. Molecular mimicry of host glycans adds further complexity to potential roles. Original drawing by R. Cummings, updated from ref. with permission from the Consortium of Glycobiology Editors.

Fig. 4.

Red Queen effects in the evolutionary diversification of glycans. Each arrowed circle represents a potential evolutionary vicious cycle, driven by a Red Queen effect, in which hosts are constantly trying to evade the more rapidly evolving pathogens that infect them. Hosts require glycans for critical cellular functions but must constantly change them to evade glycan-binding pathogens, and yet do so without impairing their own fitness. Hosts also produce soluble glycans such as mucins, which act as decoys to divert pathogens from cell surfaces; but pathogens are constantly adjusting to these defenses. Hosts recognize pathogen-specific glycans as markers of “non-self,” but pathogens can modify their glycans to more closely mimic host glycans. There are also possible secondary Red Queen effects involving host glycan-binding proteins that recognize “self”. In each of these cycles, hosts with altered glycans that can still carry out adequate cellular functions are most likely to survive. Reproduced with permission from Varki A. 2006. Cell. 126:841–845. Copyright Elsevier.

Fig. 5.

Evolutionary conflicts between alleles and individuals. For single allele-single individual, single alleles conflict with themselves when their positive effects in one context cause negative effects in another. Some examples are here. Selectins on epithelial cells bind glycans on leukocytes and guide them to sites of inflammation, but this can also be exploited by cancer cells. Regulatory or functional changes that separate conflicting tasks are expected to evolve in response. For single allele-multiple individuals, conflicts can extend across individuals that share an allele. Females that lack Neu5Gc raise antibodies against it. Males that lack Neu5Gc have higher rates of fertilization, and females have lower rates. Individual-specific regulation could resolve these conflicts. For multiple genes-single individual, selfish alleles can bias reproduction in their favor at the cost of individual reproduction, causing conflict with other genes in the genome. Mutant alleles that favor heterozygotes are passed more often than expected but increase the risk of congenital disorders of glycosylation. Other genes are selected to suppress the selfish allele, often by modification of chromosomal recombination and linkage. For multiple genes-multiple individuals, molecular markers of self cause cells to direct benefits toward identical genetic relatives, but they can be exploited by pathogen mimics. Co-evolution is a common outcome, as hosts develop more reliable markers of self, and pathogens develop more effective molecular mimics. Reproduced with permission from Springer and Gagneux, 2013, J Biol Chem, 288:904–6911.

Fig. 6.

Contrasts in early approaches to the discovery and characterization of proteins and glycans. Compared to the robust and relatively easy interdirectional progress in the early study of proteins, often originating from initial knowledge of their functions (upper panel), early approaches to the discovery and characterization of glycans (lower panel) did not often originate from functional clues. See text for discussion.

Fig. 7.

Approaches towards elucidating biological roles of glycans. The figure assumes that a specific biological role is being mediated by recognition of a certain glycan structure by a specific glycan-binding protein. Clues about biological roles could be obtained by a variety of different approaches. For detailed discussion of each approach, see the original reference. Not shown are newer methods taking advantage of the power of chemoenzymatic synthesis and the introduction of modified sugars with bioorthogonal reporter groups into biological systems. Drawing by R. Cummings, updated from ref. with permission from the Consortium of Glycobiology Editors.