Summary
Nature makes use of covalent additions of functional groups to proteins for regulating essential processes like cellular signalling and protein folding/degradation. Most of these post-translational modifications (PTMs) are enzymatically-reversible, with the coupled catalytic processes being fulfilled by antagonistic enzymes (e.g., methylase-demethylase pair). This dynamic behaviour allows for the correct metabolic equilibrium, as an unbalanced PTM-machinery is indicative of some severe diseases. Such a complex auto-regulated system is the result of millions of years of evolution that has allowed for highly efficient and site-selective functionalizations. Nevertheless, selective covalent bond formation in a substrate with multiple competitive sites is an intricate endeavour in the absence of auxiliary enzymes or other sacrificial agents. Dynamic Covalent Chemistry could be a major asset for overcoming this research bottleneck, as the reversible nature of the reactions involved can drive the functionalization to the most thermodynamically favoured site.
Most proteins contain Lys (K) residues with terminal amino groups suitable for derivatization. In particular, histone K-PTMs are crucial for controlling gene expression, with the most common modifications being acetylation and methylation. The proposed work will explore the reversible modification of histones using aldehydes that contain within their structure the functional groups required for the recognition by biological “readers”. For instance, aldehydes with carboxylate and trimethylated ammonium groups will be examined to mimic naturally occurring K-succinylation and K-trimethylation. This approach is still unexploited due to the lability of imine bonds in physiological water. However, several important biological processes are governed by the formation of imino/iminium reversible bonds with pyridoxal-5′-phosphate (PLP) derivatives, inferring that this sort of chemistry is possible in protein microenvironments.
Most proteins contain Lys (K) residues with terminal amino groups suitable for derivatization. In particular, histone K-PTMs are crucial for controlling gene expression, with the most common modifications being acetylation and methylation. The proposed work will explore the reversible modification of histones using aldehydes that contain within their structure the functional groups required for the recognition by biological “readers”. For instance, aldehydes with carboxylate and trimethylated ammonium groups will be examined to mimic naturally occurring K-succinylation and K-trimethylation. This approach is still unexploited due to the lability of imine bonds in physiological water. However, several important biological processes are governed by the formation of imino/iminium reversible bonds with pyridoxal-5′-phosphate (PLP) derivatives, inferring that this sort of chemistry is possible in protein microenvironments.
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| Web resources: | https://cordis.europa.eu/project/id/101151945 |
| Start date: | 01-10-2024 |
| End date: | 30-09-2026 |
| Total budget - Public funding: | - 195 914,00 Euro |
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Original description
Nature makes use of covalent additions of functional groups to proteins for regulating essential processes like cellular signalling and protein folding/degradation. Most of these post-translational modifications (PTMs) are enzymatically-reversible, with the coupled catalytic processes being fulfilled by antagonistic enzymes (e.g., methylase-demethylase pair). This dynamic behaviour allows for the correct metabolic equilibrium, as an unbalanced PTM-machinery is indicative of some severe diseases. Such a complex auto-regulated system is the result of millions of years of evolution that has allowed for highly efficient and site-selective functionalizations. Nevertheless, selective covalent bond formation in a substrate with multiple competitive sites is an intricate endeavour in the absence of auxiliary enzymes or other sacrificial agents. Dynamic Covalent Chemistry could be a major asset for overcoming this research bottleneck, as the reversible nature of the reactions involved can drive the functionalization to the most thermodynamically favoured site.Most proteins contain Lys (K) residues with terminal amino groups suitable for derivatization. In particular, histone K-PTMs are crucial for controlling gene expression, with the most common modifications being acetylation and methylation. The proposed work will explore the reversible modification of histones using aldehydes that contain within their structure the functional groups required for the recognition by biological “readers”. For instance, aldehydes with carboxylate and trimethylated ammonium groups will be examined to mimic naturally occurring K-succinylation and K-trimethylation. This approach is still unexploited due to the lability of imine bonds in physiological water. However, several important biological processes are governed by the formation of imino/iminium reversible bonds with pyridoxal-5′-phosphate (PLP) derivatives, inferring that this sort of chemistry is possible in protein microenvironments.
Status
SIGNEDCall topic
HORIZON-MSCA-2023-PF-01-01Update Date
25-11-2024
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