Ding Tiandi, Zhi Ying, Xie Weilin, Yao Qingqiang, Liu Bo
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, PR China.
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, PR China.
Eur J Med Chem. 2021 Mar 5;213:113164. doi: 10.1016/j.ejmech.2021.113164. Epub 2021 Jan 8.
Sphingosine kinases (SphKs) are lipid kinases that catalyze the phosphorylation of sphingosine (Sph) to sphingosine-1-phosphate (S1P). As a bioactive lipid, S1P plays a role outside and inside the cell to regulate biological processes. The overexpression of SphKs is related to a variety of pathophysiological conditions. Targeting the S1P signaling pathway is a potential treatment strategy for many diseases. SphKs are key kinases of the S1P signaling pathway. The SphK family includes two isoforms: SphK1 and SphK2. Determination of the co-crystal structure of SphK1 with various inhibitors has laid a solid foundation for the development of small molecule inhibitors targeting SphKs. This paper reviews the differences and connections between the two isoforms and the structure of SphK1 crystals, especially the structure of its Sph "J-shaped" channel binding site. This review also summarizes the recent development of SphK1 and SphK2 selective inhibitors and the exploration of the unresolved SphK2 structure.
鞘氨醇激酶（SphKs）是一种脂质激酶，可催化鞘氨醇（Sph）磷酸化为1-磷酸鞘氨醇（S1P）。作为一种生物活性脂质，S1P在细胞内外发挥作用以调节生物过程。SphKs的过表达与多种病理生理状况相关。靶向S1P信号通路是许多疾病的潜在治疗策略。SphKs是S1P信号通路的关键激酶。SphK家族包括两种亚型：SphK1和SphK2。确定SphK1与各种抑制剂的共晶体结构为开发靶向SphKs的小分子抑制剂奠定了坚实基础。本文综述了这两种亚型之间的差异与联系以及SphK1晶体的结构，特别是其Sph“J形”通道结合位点的结构。本综述还总结了SphK1和SphK2选择性抑制剂的最新进展以及对尚未解析的SphK2结构的探索。
