Diphtheria toxin-like human ADP-ribosyltransferases (ARTDs), also known as poly (ADP-ribose) polymerases (PARPs) are enzymes that catalyze a covalent modification of target proteins – ADP-ribosylation. In the reaction NAD+ cofactor is cleaved to nicotinamide and ADP-ribose. An ADP-ribosyl group is attached to the target protein in the initiation reaction or to the growing polymer chain in the elongation reaction (Figure 1). This modification changes properties of the target protein. ARTDs modify various proteins and one important target of an ARTD is typically itself through an automodification reaction. The resulting ADP-ribose polymer interacts with various proteins. The polymer is metabolized by glucohydrolases that limit the time of the signalling event. These, together with many protein targets of the ARTDs, make ADP-ribosylation an increasingly important signalling mechanism.
Figure 1. Simplified mechanism of signalling by ARTDs. Many target proteins have been identified and typically the enzymes also modify themselves through automodification.
The human ARTD enzyme family consists of 18 proteins. This protein family can be further divided according to sequence similarity and according to additional domains. It was recently discovered that most of the enzymes are not polymerases and they can only catalyze the transfer of one ADP-ribose unit to the target molecule. The human enzyme family can thus be divided into polymerases (ARTD1–6), mono ADP-ribosyltransferases (mARTDs; ARTD6–18) and the probably inactive ARTD7/13.
The widely studied human enzyme ARTD1/PARP-1 is involved in many processes, but it is mainly known for its function in the DNA repair mechanism. On the other hand, ARTD1 is also linked to death of the cell, as over-activation of ARTD1, due to extensive DNA damage, leads to cell death. The involvement of ARTD1 in DNA repair implies that inhibitors could be used to enhance the effects of anticancer drugs, whereas the involvement in cell death suggests that inhibitors could be used in injuries and in inflammation. These effects have resulted in a lot of interest in the development of new ARTD1 inhibitors, and medicinal chemistry efforts by academics and by pharmaceutical companies have resulted in development of highly potent ARTD1 inhibitors. ARTD1 inhibitors or “PARP inhibitors” developed for various cancers by different companies are currently in clinical trials, but other members of the ARTD family also have functions that could be potentially utilized in therapeutics.
Viimeksi päivitetty: 28.10.2016