Lai Xuelei, Wichers Harry J, Soler-Lopez Montserrat, Dijkstra Bauke W
Laboratory of Biophysical Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
ESRF-The European Synchrotron, 71 Avenue des Martyrs, 38000, Grenoble, France.
Chemistry. 2018 Jan 2;24(1):47-55. doi: 10.1002/chem.201704410. Epub 2017 Nov 28.
Melanin is the main pigment responsible for the color of human skin, hair and eye. Its biosynthesis requires three melanogenic enzymes, tyrosinase (TYR), and the tyrosinase-related proteins TYRP1 and TYRP2. The difficulty of isolating pure and homogeneous proteins from endogenous sources has hampered their study, and resulted in many contradictory findings regarding their physiological functions. In this review, we summarize recent advances on the structure and function of TYR and TYRPs by virtue of the crystal structure of human TYRP1, which is the first available structure of a mammalian melanogenic enzyme. This structure, combined with tyrosinase structures from other lower eukaryotes and mutagenesis studies of key active site residues, sheds light on the mechanism of TYR and TYRPs. Furthermore, a TYRP1-based homology model of TYR provides a high-quality platform to map and analyze albinism-related mutations, as well as the design of specific antimelanogenic compounds. Finally, we provide perspectives for future structure/function studies of TYR and TYRPs.
黑色素是决定人类皮肤、头发和眼睛颜色的主要色素。其生物合成需要三种黑色素生成酶，即酪氨酸酶（TYR）以及酪氨酸酶相关蛋白TYRP1和TYRP2。从内源性来源分离出纯的和均一的蛋白质存在困难，这阻碍了对它们的研究，并导致了许多关于其生理功能的相互矛盾的发现。在本综述中，我们借助人类TYRP1的晶体结构（这是首个获得的哺乳动物黑色素生成酶的结构），总结了TYR和TYRPs在结构和功能方面的最新进展。该结构与来自其他低等真核生物的酪氨酸酶结构以及关键活性位点残基的诱变研究相结合，揭示了TYR和TYRPs的作用机制。此外，基于TYRP1的TYR同源模型为定位和分析白化病相关突变以及设计特定的抗黑色素生成化合物提供了一个高质量的平台。最后，我们为TYR和TYRPs未来的结构/功能研究提供了展望。
