Inhibitors of nicotinamide N-methyltransferase designed to mimic the methylation reaction transition state
| Autor: | van Haren, Matthijs J, Taig, Rebecca, Kuppens, Jilles, Sastre Toraño, Javier, Moret, Ed E, Parsons, Richard B, Sartini, Davide, Emanuelli, Monica, Martin, Nathaniel I, Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery |
|---|---|
| Přispěvatelé: | Chemical Biology and Drug Discovery, Afd Chemical Biology and Drug Discovery |
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular Niacinamide 0301 basic medicine Methyltransferase Stereochemistry Nicotinamide N-methyltransferase Biochemistry 03 medical and health sciences chemistry.chemical_compound Nicotinamide N-Methyltransferase Humans Enzyme Inhibitors Physical and Theoretical Chemistry chemistry.chemical_classification Metabolic function Nicotinamide biology Transition (genetics) Organic Chemistry Active site Methylation 030104 developmental biology Enzyme chemistry Drug Design biology.protein |
| Zdroj: | Van Haren, M J, Taig, R, Kuppens, J, Sastre Toraño, J, Moret, E E, Parsons, R B, Sartini, D, Emanuelli, M & Martin, N I 2017, ' Inhibitors of nicotinamide : N-methyltransferase designed to mimic the methylation reaction transition state ', ORGANIC AND BIOMOLECULAR CHEMISTRY, vol. 15, no. 31, pp. 6656-6667 . https://doi.org/10.1039/c7ob01357d Organic and Biomolecular Chemistry, 15(31), 6656. Royal Society of Chemistry |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c7ob01357d |
| Popis: | Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyses 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. We here describe the systematic development of NNMT inhibitors derived from the structures of the substrates involved in the methylation reaction. By covalently linking fragments of the NNMT substrates a diverse library of bisubstrate-like compounds was prepared. The ability of these compounds to inhibit NNMT was evaluated providing valuable insights into the structural tolerances of the enzyme active site. These studies led to the identification of new NNMT inhibitors that mimic the transition state of the methylation reaction and inhibit the enzyme with activity on par with established methyltransferase inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|