Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-L-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides an indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In the search for structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC₅₀ values as low as 229 nM. The peptides were also found to downregulate MNA production in cellular assays. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT.

中文翻译：

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大环肽作为烟酰胺 N-甲基转移酶 (NNMT) 的变构抑制剂

烟酰胺N-甲基转移酶 (NNMT) 使用S-腺苷-L-甲硫氨酸 (SAM) 作为甲基供体，将烟酰胺甲基化以形成 1-甲基烟酰胺 (MNA) 。NNMT 在健康和疾病状态中作用的复杂性正在慢慢被阐明，并表明 NNMT 可能是多种疾病（包括癌症、糖尿病和肥胖症）的有趣治疗靶点。迄今为止描述的大多数 NNMT 抑制剂在结构上与其底物之一或两者相关。在寻找结构多样的 NNMT 抑制剂时，使用 mRNA 展示筛选技术来鉴定与 NNMT 结合的大环肽。以这种方式鉴定的几种环肽显示出对 NNMT 的有效抑制，IC ₅₀值低至 229 nM。还发现这些肽在细胞测定中下调 MNA 的产生。有趣的是，底物竞争实验表明，这些环肽抑制剂与 SAM 或 NA 均不具有竞争性，表明它们可能是第一个报道的 NNMT 变构抑制剂。