Harikanth Venkannagari

Åbo Akademi University
Supervisor: Lari Lehtiö
Funding: other
Date: 2011-01-01

Mono-ADP-ribosyltransferases of the human ARTD family as potential drug targets

Human ADP-ribosyl transferases (ARTDs) form a 18 member enzyme family which add ADP-ribose units to target proteins. This modification is understood to regulate DNA repair, transcription, chromatin modification, cell apoptosis and gene expression (Hakmé et al. 2008). NAD+ acts as a ligand and supplies the ADP-ribose for the reaction. Diphtheria toxin-like ARTDs include polymerases that modify substrate proteins by covalently adding a polymer of ADP-ribose units to them while mono-ADP-ribosyltransferases (mARTDs) modify their substrates by transferring a single ADP ribose unit. ARTD's 1-6 are polymerases while ARTD7-8, ARTD10-12 and ARTD14-16 are mARTDs lacking the conserved catalytic glutamate residue present in ARTD1-6. ARTD9 and ARTD13 are thought to be inactive (Kleine et al. 2008).

A lot of research has focused on ARTDs with polymerase activity because of their roles in gene regulation, DNA repair, and protein degradation and also because of their pharmaceutical importance in treating diseases like cancer, cardiac ischemia, and diabetes (Ferraris 2010). Very little is known and understood about mARTDs and recent studies indicate that they have very important roles to play in a number of cellular activities like signalling, gene regulation, cell proliferation and immunity (Till et al. 2008). ADP-ribosylation changes the properties of the target enzyme typically by interfering with the binding to other macromolecules. It also creates new interactions with different protein modules like macro domains (Neuvonen & Ahola 2009).

The aim of the project is first to develop accurate and efficient activity and binding assays for studying mono-ADP-ribosylation. Inhibitor screening will then be combined with structural studies in order to develop selective inhibitors. These inhibitors will then be used to study the biological roles of the isoenzymes and to reveal the therapeutic potential of inhibiting mARTDs.

References