21 February 2006

Glycomics: The next level of Gene Expression after Genomics and Proteomics?

Move over genomics, and proteomics. Now there is glycomics, the study of the carbohydrates in the cell. This is but another level of gene expression, and many of the the same tools used in genomics and proteomics are being called into service in understanding this new level of complexity. Expect many new pharmaceuticals to come from an understanding of this very complex field.

Though they are not charged with storing genetic information like DNA or acting as enzymatic workhorses like proteins, carbohydrates nevertheless do carry information and are responsible for important biological functions, playing a central role in many types of intercellular communication events, protein folding, cell adhesion, and immune recognition.

One of the most important frontiers of basic research in biology today is to understand the human glycome--all of the types of carbohydrate structures in the human body and what they do. This is a profoundly difficult endeavor. The total number of carbohydrate structures in humans may be 10,000 to 20,000, although it is hard to fix a hard number to this, says Paulson. Nevertheless, he adds, "We think understanding the glycome is possible now. We didn't think that three years ago."

From another source:

As the human genome sequence is nearly deciphered, it is important to turn the attention to the physiological functions of the genes. Thus, the study of the gene products, the proteins, is the next big challenge. The proteins, however, are not the final gene products in many cases. It has been shown that carbohydrates participate in post-translational modifications and in many other functional regulations, hence the study of the glycome, the entire collection of carbohydrates is essential in order to determine the functions of all genes, and will greatly enhance the field of chemical genetics.

By analogy with the term ‘proteome’, the term ‘glycome’ has been coined for the glycan repertoire of an organism. Also, in the wake of ‘genomics’ and ‘proteomics’, the word ‘glycomics’ has become the trendy term for the characterisation by structure and function of the glycans in the system under study. In this section of Current Opinion in Structural Biology, four reviews take us to the frontiers of knowledge on the biosyntheses and roles of glycosaminoglycans (GAGs), and two of the exotic decorations of glycoproteins, O-mannosyl and O-GlcNAc glycans. Two reviews focus on new approaches to the study of carbohydrate–protein interactions: carbohydrate microarrays to examine proteins for carbohydrate-binding activity and NMR spectroscopy for analyses of the structural details of carbohydrate–protein interactions in solution.

* Complex glycans are important modulators of numerous biological processes, ranging from organ development to wound healing to the modification of diseases such as cancer. Although there are some exceptions, glycans do not generally control biological processes in a digital 'on or off' manner; rather, they 'fine-tune' biological functions.

* Complex glycans are either linear or branched structures that can exist alone or attached to other biomolecules. Owing to variation in branching patterns and in the individual monosaccharides that comprise the chain, glycans are information-dense biomolecules.

* Recent advances in several areas of research — including the development of analytical techniques, numerous genetic studies, new synthetic strategies and the advent of bioinformatics platforms — have raised the exciting possibility that glycan-based drugs could be developed for many diseases.

* Structure–function studies in this area have already led to important advances, both scientifically and in terms of drug development. Two examples of the latter are the development of second-generation antithrombotics with increased efficacy and increased clinical usefulness, and the development of improved forms of glycoprotein drugs.

* The US National Institutes of Health has recently sponsored the development of a consortium that brings together leaders in the field of glycan chemistry and biology to systematically catalogue and study glycan structure and function. This endeavour promises to provide a wealth of important information for the development of novel therapeutics and diagnostics, in a similar way to other federally sponsored initiatives in genomics and proteomics.

...It has become increasingly clear over the past decade that GAGs at the cell surface influence the interactions of cells with their immediate environment in ways that are sensitive to the fine structure of GAGs with respect to monosaccharide sequence and sulfation pattern. At the molecular level, the degree of specificity with which heparan sulfate (HS) sequences interact with, for instance, fibroblast growth factors and their receptors is a continuing source of interest and controversy. Studies at the whole-organism level have revealed the consequences of the absence of several of the enzymes of GAG biosynthesis, including some specific sulfotransferases. These knockout experiments have demonstrated that sulfate substitutions at particular positions on the GAG structure are necessary for specific aspects of embryonic development. Kusche-Gullberg and Kjellén present a concise but comprehensive summary of recent work on the identification and characterisation of the sulfotransferases that form the intricate GAG sulfation patterns.

Specific interactions between extracellular proteins and the GAGs heparin and HS are recognized to be dependent on variations in the details of sequence and substitution. In contrast, the galactosaminoglycans, known as chondroitin sulfates (CSs), have, in the past, been assumed to play a relatively inert, structural role, particularly in the extracellular matrix. Sugahara and co-authors review recent literature showing that CS, as well as HS, may be involved in development and morphogenesis, wound repair and infection, and that this involvement is dependent on patterns of sulfate substitution. CS in the central nervous system may act as a barrier to neuronal cell growth; the use of chondroitin-degrading enzymes to permit the regrowth of nervous tissue after, for example, spinal cord damage may be of considerable medical significance. On the other hand, some over-sulfated CS sequences present in the brain bind to growth factors and may play a part in neuritogenesis. Work on the model organism C. elegans has shown that GAGs are essential for correct development; the absence of chondroitin synthase (induced by RNAi of the sqv-5 gene, orthologous to human ChSy) can lead to serious anomalies, such as gonadal malformation and a profound disregulation of cell division in the early stages of embryogenesis, by mechanisms not yet fully understood. A current topic of research concerns the involvement of CS with specific sulfation patterns in infection, with particular reference to malaria in pregnancy.

In comparison with genomics and proteomics, the advancement of glycomics has faced unique challenges in the pursuit of developing analytical and biochemical tools and biological readouts to investigate glycan structure-function relationships. Glycans are more diverse in terms of chemical structure and information density than are DNA and proteins. This diversity arises from glycans' complex nontemplate-based biosynthesis, which involves several enzymes and isoforms of these enzymes. Consequently, glycans are expressed as an 'ensemble' of structures that mediate function. Moreover, unlike protein-protein interactions, which can be generally viewed as 'digital' in regulating function, glycan-protein interactions impinge on biological functions in a more 'analog' fashion that can in turn 'fine-tune' a biological response. This fine-tuning by glycans is achieved through the graded affinity, avidity and multivalency of their interactions. Given the importance of glycomics, this review focuses on areas of technologies and the importance of developing a bioinformatics platform to integrate the diverse datasets generated using the different technologies to allow a systems approach to glycan structure-function relationships.


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