Speakers
Nathaniel I. Martin
(Utrecht Institute for Pharmaceutical Sciences, Utrecht University)
Date
03
Apr 2018
Time
14:00:00
28 Rue du Docteur Roux, Paris, France
Address
Building: CFJ
Location
2018-04-03 14:00:00
2018-04-03 15:00:00
Europe/Paris
Bisubstrate analogues as N-methyltransferase inhibitors and tool compounds for structural studies
The N-methyltransferases represent a large enzyme family that functions by specifically transferring a methyl group from the cofactor S-adenosyl-l-methionine (AdoMet) to a nitrogen center in a target protein or small molecule. The Martin lab […]
28 Rue du Docteur Roux, Paris, France
Paola Arimondo
paola.arimondo@pasteur.fr
About
The N-methyltransferases represent a large enzyme family that functions by specifically transferring a methyl group from the cofactor S-adenosyl-l-methionine (AdoMet) to a nitrogen center in a target protein or small molecule. The Martin lab is interested in developing new probe molecules for studying a variety of different N-methyltansferases including the protein arginine N-methyltransferases (PRMTs). PRMTs are responsible for the methylation of the guanidine moiety of arginine side chains in target proteins. Most notable is the PRMT-mediated methylation of arginine residues found in histone proteins which can lead to chromatin remodelling and influence gene transcription. A growing body of evidence now implicates dysregulated PRMT activity in a number of diseases including various forms of cancer. The development of PRMT inhibitors hold potential as a means of developing new therapeutics. This lecture will present our efforts to synthesize small molecule PRMT inhibitors designed to simultaneously occupy the binding sites of both the guanidino substrate and AdoMet cofactor. Potent inhibition and surprising selectivity was observed when testing these compounds against a panel of methyltransferases.1
An atomic-scale understanding of the PRMT catalytic mechanism is also crucial for both fundamental biological and pharmacological applications. Despite intense efforts, crystal structures of PRMT complexes with long peptides and full-length substrates have not been solved due to their inherent instability. To address this issue we have recently developed peptide-based transition state mimics that form stable complexes with the PRMT enzyme CARM1 resulting in high-resolution co-crystal structures. These findings provide an exciting new approach to understanding PRMT substrate recognition and the regulation of arginine methylation.2
Also to be presented is some of our recent work aimed at developing small molecule inhibitors of nicotinamide N-methyltranserase (NNMT).3,4 NNMT is an enzyme that catalyzes the methylation of nicotinamide to form N’-methylnicotinamide. Both NNMT and its methylated product have recently been linked to a variety of diseases, suggesting a role for the enzyme as a therapeutic target beyond its previously ascribed metabolic function in detoxification. The lecture will cover our attempts to systematically develop NNMT inhibitors derived from the structures of the substrates involved in the methylation reaction. By covalently linking fragments of the NNMT substrates bisubstrate-like compounds were prepared. The ability of these compounds to inhibit NNMT provides valuable insights into the structural tolerances of the enzyme active site.
Location
Building: CFJ
Address: 28 Rue du Docteur Roux, Paris, France