Dissertation

Synthetic Methodology Towards ADP-Ribosylation Related Molecular Tools

Phosphorylation affects all four major biomolecules – proteins, lipids, carbohydrates and nucleic acids – and plays a pivotal role in the most fundamental cellular functions.

Author: Engelsma, S.B.
Date: 05 September 2019
Links: Thesis in Leiden Repository

Phosphorylation affects all four major biomolecules – proteins, lipids, carbohydrates and nucleic acids – and plays a pivotal role in the most fundamental cellular functions. A prime example of a PTM that caught a lot of scientific interest is adenosine diphosphate ribosylation (ADP-ribosylation), carried out by the PARP family of enzymes. ADP-ribosylation is an indirect form of (pyro)phosphorylation, where a monomer or polymer of ADPr is attached to an acceptor protein. The process of ADP-ribosylation has been linked to DNA damage repair, telomere maintenance and regulation of apoptosis, highlighting it of biomedical importance, most notably in relation to cancer therapy and inflammatory disorders. Well-defined phosphorylated molecular tools have already proven to be effective at elucidating the molecular mechanisms behind both normal and pathological cell function. However, the natural pyrophosphate group is inherently susceptibility to hydrolysis, trans-esterification and enzymatic cleavage. This property limits their use through possible premature degradation or restricted synthetic accessibility. The research described in this thesis focuses on the development of new molecular tools, primarily intended to facilitate the study of adenosine diphosphate ribosylation. In this context new reagents and methodologies have been developed for the synthesis of stabilized pyrophosphorylated bioisosteres.