# Discovery of Glycation-Derived Cross-links at Arginine

## TL;DR

Researchers discovered a new type of glycation cross-link called MIDAL, which could be important in age-related diseases and can form in living cells.

## Contribution

The study introduces a novel peptide platform for discovering and analyzing previously unknown glycation cross-links.

## Key findings

- A new Arg–Arg cross-link called MIDAL was identified as a major AGE under specific conditions.
- MIDAL can form in biocompatible conditions and persists for over 3 days.
- MIDAL is produced in living mammalian cells, indicating physiological relevance.

## Abstract

Glycation cross-links account for more than 40% of all
known advanced
glycation end products (AGEs) and are correlated with many age-related
diseases. Despite much interest, cross-linking AGEs (xl-AGEs) remain
poorly understood, as they have been challenging to discover, prepare,
and quantify. Here, we describe a peptide platform that is ideally
suited for the study of xl-AGEs, which not only facilitates direct
comparisons between the prevalence of known xl-AGEs and other AGEs
but also enables the discovery of previously unknown xl-AGEs. In this
study, we use this platform to discover the first known Arg–Arg
xl-AGEs, a pair of
m
ethylglyoxal-derived
dihydroxy
i
mi
d
azolidine hemi
a
cetal
cross
l
ink, or MIDAL, isomers.
We show that MIDAL can become the major AGE, exceeding levels of all
other AGEs, for substrates in which two Arg glycation sites are optimally
positioned. We further demonstrate that MIDAL is readily and reversibly
generated in biocompatible conditions, persisting with a half-life
of more than 3 days. We also demonstrate that MIDAL can form in living
mammalian cells, suggesting that it has the potential to be a dynamic,
physiologically relevant and functional xl-AGE. This work therefore
offers important insights about MIDAL formation and describes a versatile
platform to enable the study of xl-AGEs under a variety of conditions.
We expect that it will be highly useful for further discovery of biologically
relevant glycation cross-links that are yet to be identified.