Digging in to the Biochemistry of Glucosepane

Advanced glycation end-products (AGEs) are forms of waste produced by the ordinary operation of metabolism, in which sugars attach to proteins to form hardy compounds that in some cases are a challenge to remove. In humans glucosepane is by far the most prevalent form of AGE, and its growing presence with age causes increased levels of chronic inflammation, and a loss of elasticity and function in many tissues.

Very few researchers are presently working on ways to remove glucosepane, which is why the SENS Research Foundation funds a program aimed at making progress towards this goal. A therapy to clear glucosepane would remove this contribution to degenerative aging, and is thus a needed part of any future toolkit of rejuvenation treatments.

Ageing and diabetes share a common deleterious phenomenon, the formation of Advanced Glycation Endproducts (AGEs), which accumulate predominantly in collagen due to its low turnover. Though the general picture of glycation has been identified, the detailed knowledge of which collagen amino acids are involved in AGEs is still missing. In this work we use an atomistic model of a collagen fibril to pinpoint, for the first time, the precise location of amino acids involved in the most relevant AGE, glucosepane.

The results show that there are 14 specific lysine-arginine pairs that, due to their relative position and configuration, are likely to form glucosepane. We find that several residues involved in AGE crosslinks are within key collagen domains, such as binding sites for integrins, proteoglycans and collagenase, hence providing molecular-level explanations of previous experimental results showing decreased collagen affinity for key molecules. Altogether, these findings reveal the molecular mechanism by which glycation affects the biological properties of collagen tissues, which in turn contribute to age- and diabetes-related pathological states.

Link: http://dx.doi.org/10.1016/j.matbio.2013.09.004


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