Undoing Sugar Damage: First Synthesis Of Culprit Glucosepane

Sugars may taste divine, but they're also highly reactive molecules that progressively stiffen your body in a process called glycation. Scientists have now synthesised the primary molecule formed in glycation for the first time, leading to hope that drugs can be designed to break them apart.  

What is glycation?

In our bodies sugars continuously react with proteins in an unregulated manner in a process known as glycation. This leads to the formation of abnormal chemical modifications of the protein which may impair its normal function. These sugar-modifications are collectively known as advanced glycation end products (AGEs) and can be subdivided in two main categories. First are the modifications that affect a single amino acid. The second category consists of modifications that link two amino acids together in a structure called a crosslink. 

Glycation isn't the same as glycosylation

It is important to differentiate AGEs from the regulated, enzymatic addition of sugars to proteins, a process known as glycosylation, which also takes place in our cells. The sugar-modifications caused by glycosylation have a very different chemical structure from those caused by glycation and hence also behave differently. Glycosylation is necessary for the normal properties and function of proteins while glycation impairs the normal properties and function of the proteins.  

How does glycation contribute to aging?

There is a progressive increase with age in the amount of AGEs present on long-lived proteins such as the collagen in our tendons. Shorter lived proteins also fall prey to glycation but their turnover prevents their accumulation. AGEs make the long-lived proteins even more resistant against degradation leading to a fast-forward cycle of progressively more glycation damage. AGEs negatively influence tissue function by increasing the stiffness leading for example to stiffer arteries. They can also bind to receptors on our cells leading to the production of free radicals and inflammation. Higher levels of AGEs have been found in patients suffering from several diseases including diabetes, cardiovascular disease and Alzheimer's. That AGEs may play a role in aging is illustrated by the observation that AGE levels negatively correlate with maximal lifespan across animal species.    

Glucosepane levels in human skin collagen rise with age. Redrawn from Sell et al, J Biol Chem. 2005 Apr 1;280(13):12310-5. PMID: 15677467

A step forward

In a new study published in the journal Science, researchers at the department of chemistry at Yale University announce the chemical synthesis of glucosepane. Glucosepane is believed to be the most abundant glycation crosslink in the human body. So now for the first time we have access to chemically pure glucosepane which will allow us to design specific antibodies, screen for crosslink breakers, and further explore the biology of this important crosslink.