van Haren Matthijs J, Taig Rebecca, Kuppens Jilles, Sastre Toraño Javier, Moret Ed E, Parsons Richard B, Sartini Davide, Emanuelli Monica, Martin Nathaniel I
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Org Biomol Chem. 2017 Aug 9;15(31):6656-6667. doi: 10.1039/c7ob01357d.
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.
烟酰胺N-甲基转移酶（NNMT）是一种催化烟酰胺甲基化形成N'-甲基烟酰胺的酶。最近，NNMT及其甲基化产物都与多种疾病有关，这表明该酶作为一种治疗靶点，其作用超出了先前认为的在解毒方面的代谢功能。我们在此描述了基于甲基化反应中涉及的底物结构系统开发的NNMT抑制剂。通过共价连接NNMT底物的片段，制备了一个多样化的双底物样化合物库。评估了这些化合物抑制NNMT的能力，为酶活性位点的结构耐受性提供了有价值的见解。这些研究导致鉴定出了新的NNMT抑制剂，它们模拟甲基化反应的过渡态，并且抑制该酶的活性与已有的甲基转移酶抑制剂相当。
