April 2013

Glycans: the underappreciated building block of life

Cover of the 2013 JBC thematic miniseries Glycobiology & Extracellular MatricesGlycans are saccharides that can be attached to a wide variety of biological molecules through an enzymatic process called glycosylation to augment their function. Of the four fundamental building blocks of life, proteins, carbohydrates (glycans), lipids and nucleic acids, glycans have received the least attention from researchers. Glycans are found in Archaea, bacteria and eukaryotes, and their diverse functions contribute to physical and structural integrity, extracellular matrix formation, signal transduction, protein folding and information exchange between cells (and pathogens). A recent issue of the Journal of Biological Chemistry highlighted the important and diverse biological functions of glycans in a thematic minireview series organized by Associate Editor Gerald W. Hart.
In the first article, authors Stevan Springer and Pascal Gagneux discuss how evolution shaped glycan diversity. The regulatory capacity and structural diversity of glycans surpasses those of other biological molecules. The authors argue that glycan diversity stems from their role as mediators of cellular interaction. Glycans are the predominant molecule on the cell surface and serve as the first point of contact between a cell and other cells, the extracellular matrix and pathogens. The heightened evolutionary pressure of being at the front lines of cellular collaboration and conflict most likely led to the diversification of glycans, the authors argue.
Harald Nothaft and Christine M. Szymanski discuss the possibilities of exploiting bacterial N-glycosylation to create new vaccines and diagnostics in their review. In the never-ending fight against disease, it is essential that we continue to enhance our repertoire of drugs and vaccines. The most effective and safest vaccines are those in which a polysaccharide antigen is attached covalently to a protein carrier molecule. However, the process of generating these conjugate vaccines is expensive, time-consuming and sometimes inefficient. The authors review the possibility of using bacteria to glycoengineer effective compound vaccines similar to how human insulin is genetically engineered in E. coli.
Duy T. Tran and Kelly G. Ten Hagen in their review focus on the role of mucin-type O-glycosylation during eukaryotic development to shed light on its role in human disease and disability. O-glycosylation is one of the two most abundant forms of glycosylation (N-glycosylation being the other) and plays an essential role in protein secretion, stability and function. O-glycans are found in distinct locations within developing tissues and even show developmental stage-specific changes in branching. A handful of human diseases, including tumor formation and progression, are attributed to defects in O-glycosylation. The authors argue that a better understanding of O-glycosylation during development will lead to a better understanding of human disease.
In the penultimate review, Lance Wells highlights the role of glycans in the group of debilitating and life-shortening disorders known as congenital muscular dystrophy, or CMD. Both membrane proteins and the ECM are highly glycosylated, and O-glycans are essential for proper ECM function and communication between cells and the ECM. Several forms of CMD are known to result from dysfunctional O-glycosylation of membrane and ECM proteins; however, one-third of CMDs arise from an unknown genetic etiology. Future studies are needed to appreciate fully the complex role O-glycosylation plays in cell-to-ECM communication and CMD.
In the last review, Hudson H. Freeze discusses bridging the gap between identifying genes responsible for disease and explaining the molecular mechanisms causing the disease. Historically, genes responsible for glycan disorders were discovered by biochemical analysis. Now, gene sequencing and high-tech gene mapping techniques can identify slightly more than 50 percent of responsible genes. A new collaboration between geneticists and glycan biochemists will lead to the discovery of many more glycosylation disorders, their molecular causes and new treatments for existing glycosylation disorders.

Joseph TianoJoseph P. Tiano (tiano233@hotmail.com) is a postdoctoral fellow at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

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