Carbohydrate complexities: advancing glycoscience

H5N1 haemagglutinin
Glycan chips have been developed over the last five years, but they only contain a minute fraction of the molecules found in nature. If one needs a well-defined carbohydrate to study a biological process, it's very difficult to obtain those carbohydrates. Professor Geert-Jan Boons
Glycoscience is essential to our understanding of biology and a field that is coming into its own, according to Professor Geert-Jan Boons of the Complex Carbohydrate Research Center…

Over the last 30 years, genomics and proteomics have received a lot of scientific interest. In the past decade, however – perhaps more so in the last five years – there has been a greater appreciation of the fact that biology is about more than just genes and proteins. The understanding is dawning that complex carbohydrates are responsible for the modulation of all biological activities and the lesser known cousin, glycomics, has come to claim its seat at the table.

The term ‘glycobiology’ was coined by Professor Raymond Dwek in 1988 to describe the coming together of carbohydrate chemistry and biochemistry. The field of glycobiology is broadly concerned with the structure, synthesis and biological function of saccharides, also referred to in this context as carbohydrates. In 2005, Anthony Merry and Catherine Merry wrote that glycoscience had finally come of age, but can it really be claimed to have done so?

Professor Geert-Jan Boons is Franklin Professor of Chemistry at the University of Georgia’s Complex Carbohydrate Research Center. He has been awarded the Whistler Award in Carbohydrate Chemistry for 2014. Professor Boons discussed the importance of glycoscience and advances in the field with ScienceOmega.com.

As well as being the markers that distinguish between blood groups in the ABO system, carbohydrates have an important role to play in human development, the molecular mechanisms of chronic disease, and cancer metastasis; indeed, carbohydrates are involved in almost every physiological and pathophysiological process.

"Over the last decade, I would say an appreciation has been developing that carbohydrates are very important and that to properly understand proteins, for example, one needs to look at post-translational modifications too."

Modifiers and mediators
 

Glycosylation – a reaction where, in biology, a carbohydrate becomes joined to a protein, lipid or other organic molecule – is of particular importance as a form of co-translational and post-translational modification. It is an enzymatic process which contributes greatly to diversity in the proteome, especially in light of the fact that 99 per cent of cell surface proteins are modified by complex carbohydrates. If a cell’s ability to attach carbohydrates to proteins is removed, the cell is no longer viable. Interactions between cells are very often mediated by carbohydrate-protein interactions, as Professor Boons highlighted.

"By the same token, the interaction of pathogens with cells is very often mediated by the interaction of a protein on a pathogen and a carbohydrate on a cell," he noted. "The way the flu virus gets into a cell, for example, is by binding to carbohydrates on the epithelial cells in our airways. Drugs such as Tamiflu work by inhibiting the interaction of influenza haemagglutinin with carbohydrates on our own cells."

It is mutations of the haemagglutinin present on the surface of the avian influenza virus, for example, that enable it to bind to human-type carbohydrates which enables the transformation into a human influenza virus.

"Almost every cell-cell interaction is mediated by carbohydrates," Professor Boons said. "If they are not present, it doesn't happen. I talked about infection, but carbohydrates also play an important role in other diseases. One of the hallmarks of cancer is that the sugars on the cell's surface change in structure, often giving cancer cells the ability to metastasise."

Proteins which are modified by complex carbohydrates are not bound to bond with one particular carbohydrate; rather there is an array of structurally similar carbohydrates to which it may bond. The position of the bond itself may vary. Unlike nucleic acids and proteins, these carbohydrates can be branched and can differ in length, so they are structurally much more complex than proteins and DNA.

"The processes whereby DNA is transcribed into RNA and RNA translated into proteins are all template-mediated," Professor Boons pointed out. "Hence when a cell makes a protein, the protein should theoretically be the same every time. Complex carbohydrates are attached to proteins through enzymes in a non-template-mediated process which results in a lot of heterogeneity."

'A lack of simple, convenient tools'


Part of the reason that carbohydrates have largely been ignored for so long is because of the difficulties these factors cause, Professor Boons related. Although techniques for studying saccharides have improved and become slightly more general in the past five to 10 years, a lack of simple, convenient tools is still one of the main obstacles facing glycoscientists and their research.

"Nowadays it is possible to buy gene chips on which every gene is present and you can study its expression," said Professor Boons. "Glycan chips have been developed over the last five years, but they only contain a minute fraction of the molecules found in nature. If one needs a well-defined carbohydrate to study a biological process, it's very difficult to obtain those carbohydrates.

"The analytical tools to determine which carbohydrate structures are found on a cell surface are still rather rudimentary and definitely not routine. Many of the tools routinely employed for protein and oligonucleotide chemistry remain too specialised for glycobiology."

The fundamental importance of glycoscience in all aspects of human development as well as disease will ensure that the field continues to draw attention and, increasingly, funding. It will certainly be a necessary focus of future research if we are to clarify how organisms work in terms of molecular, cellular and systems biology.

"If we don't take into account post-translational modifications – how proteins are modified by carbohydrates and other entities – we will not understand biology," reiterated Professor Boons. "As I mentioned, almost every disease is linked in some way to glycoscience. If we want to make real progress in the development of novel therapeutics, we need to understand the biology of complex carbohydrates in much more detail."

Medicine and health are not the only areas in which glycoscience is making its presence felt, however.

Different applications, different strengths
 

"In terms of bioenergy and converting crops into fuels, we are really talking about the conversion of carbohydrates into useful fuels," Professor Boons continued. "We would like to know much more about the way that plants form carbohydrates – i.e. biomass – and how that can be converted into useful tools."

The study of complex carbohydrates is also relevant to materials science, as Professor Boons explained.

"Right now most of the materials we make – plastics and the like – come from fossil fuels, but there has been a realisation that cellulose and other plant materials can also be employed for those sorts of purposes. They are renewable, of course, and very attractive as a replacement for fossil fuel products."

In terms of the international landscape of glycoscience research, Professor Boons expressed the belief that different countries have different strengths.

"The United States is very strong in glycobiology, while Canada is very strong in carbohydrates and infectious diseases," he said. "I think the structural biology of carbohydrates is an area of strength in Europe, where there are some particularly able chemistry groups dealing with glycans."

A report from the US National Academy of Sciences last year, entitled 'Transforming Glycoscience: A Roadmap for the Future', brought attention to the concerns of glycoscientists themselves about the status and direction of their field. It seems that greater recognition of that research which comes under the glycobiology umbrella, more awareness of the significance of this research, and a collaborative approach will have their role to play in promoting glycoscience to the position it so thoroughly deserves. 

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