Département de Pharmacochimie Moléculaire (DPM), UMR 5063, Université Grenoble Alpes, 38041 Grenoble, France.
J Med Chem. 2020 Nov 25;63(22):13428-13443. doi: 10.1021/acs.jmedchem.0c00994. Epub 2020 Aug 17.
Human tyrosinase (TYR) is the key enzyme ensuring the conversion of l-tyrosine to dopaquinone, thereby initiating melanin synthesis, i.e., melanogenesis. Although the protein has long been familiar, knowledge about its three-dimensional structure and efficient overexpression protocols emerged only recently. Consequently, for decades medicinal chemistry studies aiming at developing skin depigmenting agents relied almost exclusively on biological assays performed using mushroom tyrosinase (TYR), producing a plethoric literature, often of little useful purpose. Indeed, several recent reports have pointed out spectacular differences in terms of interaction patterns and inhibition values between TYR and TYR, including for widely used standard tyrosinase inhibitors. In this review, we summarize the last developments regarding the potential role of TYR in human pathologies, the advances in recombinant expression systems and structural data retrieving, and the pioneer generation of true TYR inhibitors. Finally, we present suggestions for the design of future inhibitors of this highly attractive target in pharmacology and dermocosmetics.
人类酪氨酸酶 (TYR) 是确保 l-酪氨酸转化为多巴醌的关键酶，从而启动黑色素合成，即黑素生成。尽管该蛋白质早已为人熟知，但直到最近才出现有关其三维结构和高效过表达方案的知识。因此，数十年来，旨在开发皮肤美白剂的药物化学研究几乎完全依赖于使用蘑菇酪氨酸酶 (TYR) 进行的生物测定，产生了大量文献，但往往没有多大实际用途。事实上，最近的几份报告指出了 TYR 和 TYR 之间在相互作用模式和抑制值方面的显著差异，包括广泛使用的标准酪氨酸酶抑制剂。在这篇综述中，我们总结了 TYR 在人类病理中的潜在作用、重组表达系统和结构数据检索方面的最新进展，以及真正的 TYR 抑制剂的开创性研究。最后，我们为设计药理学和皮肤化妆品学中这一极具吸引力的靶标未来抑制剂提出了建议。
