Abstract
The sirtuins form a superfamily of evolutionarily conserved NAD+-dependent protein N-∊-acyl-lysine (AcK) deacylases with roles in a variety of key cellular processes. Sirtuins have a broadly conserved overall structure with a catalytic site formed by a hydrophobic channel between the NAD+-binding Rossmann fold domain and a smaller Zn2+-binding domain. Schistosomes express five members of the sirtuin family and generic sirtuin inhibitors induce apoptosis and death in schistosome larvae, the disruption of adult worm pairs, inhibition of egg laying and damage to the male and female worm reproductive systems. Sirtuins in schistosomes and other parasitic flatworms present structural differences from their human orthologues that should allow the development of selective inhibitors that can be developed as drug leads.
Financial & competing interests disclosure
This work and the authors of this manuscript have been supported by funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement nos. 241865 (SEtTReND) and 602080 (A-ParaDDisE). CR, MM and RJP are supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université de Strasbourg and the Université de Lille 2, the French Infrastructure for Integrated Structural Biology (FRISBI; ANR-10-INSB-05–01) and by Instruct (ESFRI). MJ thanks the Deutsche Forschungsgemeinschaft for funding (DFG, Project P10 within RTG1976). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.