Biological Relevance of Glycosylation

More than one percent of the vertebrate genome seems to be committed to the synthesis and recognition of glycans. This, together with the increasing complexity and diversity of glycans during evolution indicates that they have many biological roles yet to be discovered. The following summary indicates that we already know a lot about the biological relevance of glycosylation.


1. Glycosylation is critical for normal development and differentiation
(A) Genetic elimination or partial abrogation of expression of each of the major classes of glycans has been shown to be lethal during murine embryogenesis.
(B) An increasing number of human genetic disorders are being recognized as caused by mutations in glycosylation pathways. The phenotypes range from mild to very severe. Some of these (now called congenital disorders of glycosylation) have been successfully treated by oral feeding of simple sugars.
(C) Genetic disruption of various outer chain determining glycosyltransferases in mice has given rise to viable animals that still have significant biological defects.

(D) In almost every animal species studied to date, recognition of egg cell surface sugars by sperm receptors is a first or early step in fertilization. Glycan recognition differences between related species might also serve as an important barrier to cross-fertilization.

2. Glycosylation is important for host relationships to microbes

(A) Most microbial pathogens and toxins access/communicate with host cells by mechanisms that include recognition of cell surface glycans.

(B) Many symbiont microbes also recognize cell surface sugars as a means to maintain symbiosis.

(C) Molecular mimicry of higher animal cell surfaces by microbial pathogens is a highly successful strategy that is mediated primarily by microbial synthesis of animal-like glycans.

(D) The protective responses of multicellular organisms to invasion by pathogens is mediated by recognition of glycans released by the pathogens.

3. Glycosylation is important for pharmacology and therapeutics

(A) The single most widely used drug in the world today consists of sugar chains (heparin). The amount used yearly is measured in tons.

(B) Biotech and pharmaceutical companies must pay very close attention to glycosylation of many recombinant biotherapeutics, since this affects their half-life, functionality and approval by regulatory agencies.

(C) Many important growth factors and cytokines interact specifically with certain glycans, markedly affecting their stability, localization to the appropriate sites, local concentration and their role in the production of gradients that, in turn, control morphogenesis.
(D) Glycans are involved in directing or modulating several important signaling pathways.
4. Glycosylation is important for cell-cell and cell matrix interactions

(A) Glycans are major physical components of the extracellular matrix and mediate critical interactions with other matrix components, as well as cell matrix interactions.
(B) Several major gene families of endogenous glycan binding proteins have been recognized. Such lectins have been shown to use sugar chains as "address codes" that determine survival and trafficking of protein molecules within cells, and for the trafficking of cells and proteins throughout the body.

(C) Altered glycosylation is a universal feature of malignancy. The changes are very selective, and some of these changes are known to directly contribute to invasion and metastasis.