Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, United States.
ACS Chem Biol. 2020 Jul 17;15(7):1747-1758. doi: 10.1021/acschembio.0c00314. Epub 2020 Jun 10.
Protein myristoylation, the addition of a 14-carbon saturated acyl group, is an abundant modification implicated in biological events as diverse as development, immunity, oncogenesis, and infections. N-Myristoyltransferase (NMT) is the enzyme that catalyzes this modification. Many elegant studies have established the rules guiding the catalysis including substrate amino acid sequence requirements with the indispensable N-terminal glycine, and a co-translational mode of action. Recent advances in technology such as the development of fatty acid analogs, small molecule inhibitors, and new proteomic strategies, allowed a deeper insight into the NMT activity and function. Here we focus on discussing recent work demonstrating that NMT is also a lysine myristoyltransferase, the enzyme's regulation by a previously unnoticed solvent channel, and the mechanism of NMT regulation by protein-protein interactions. We also summarize recent findings on NMT's role in cancer, immunity, and infections and the advances in pharmacological targeting of myristoylation. Our analyses highlight opportunities for further understanding and discoveries.
蛋白质豆蔻酰化，即添加一个 14 个碳的饱和酰基，是一种广泛存在的修饰，涉及发育、免疫、肿瘤发生和感染等多种生物学事件。N-豆蔻酰转移酶（NMT）是催化这种修饰的酶。许多精细的研究已经确定了指导催化的规则，包括底物氨基酸序列要求，其中必不可少的是 N 端甘氨酸，以及共翻译作用模式。最近技术的进步，如脂肪酸类似物、小分子抑制剂和新的蛋白质组学策略的发展，使人们对 NMT 的活性和功能有了更深入的了解。在这里，我们重点讨论最近的工作，这些工作表明 NMT 也是一种赖氨酸豆蔻酰转移酶，酶的调节由以前未被注意到的溶剂通道，以及 NMT 通过蛋白质-蛋白质相互作用的调节机制。我们还总结了 NMT 在癌症、免疫和感染中的作用以及豆蔻酰化的药理学靶向方面的最新发现。我们的分析强调了进一步理解和发现的机会。
