Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Structure. 2010 Aug 11;18(8):1054-65. doi: 10.1016/j.str.2010.05.011.
Sphingosine-1-phosphate lyase (SPL), a key enzyme of sphingolipid metabolism, catalyzes the irreversible degradation of sphingoid base phosphates. Its main substrate sphingosine-1-phosphate (S1P) acts both extracellularly, by binding G protein-coupled receptors of the lysophospholipid receptor family, and inside the cell, as a second messenger. There, S1P takes part in regulating various cellular processes and its levels are tightly regulated. SPL is a pivotal enzyme regulating S1P intracellular concentrations and a promising drug target for the design of immunosuppressants. We structurally and functionally characterized yeast SPL (Dpl1p) and its first prokaryotic homolog, from Symbiobacterium thermophilum. The Dpl1p structure served as a basis for a very reliable model of Homo sapiens SPL. The above results, together with in vitro and in vivo studies of SPL mutants, reveal which residues are involved in activity and substrate binding and pave the way to studies aimed at controlling the activity of this pivotal enzyme.
鞘氨醇-1-磷酸酶（SPL）是鞘脂代谢的关键酶，可催化鞘氨醇碱基磷酸的不可逆降解。其主要底物鞘氨醇-1-磷酸（S1P）在细胞外通过与溶血磷脂受体家族的 G 蛋白偶联受体结合，以及在细胞内作为第二信使发挥作用。在细胞内，S1P 参与调节各种细胞过程，其水平受到严格调控。SPL 是调节 S1P 细胞内浓度的关键酶，也是设计免疫抑制剂的有前途的药物靶点。我们对酵母 SPL（Dpl1p）及其第一个原核同源物（来自嗜热共生菌）进行了结构和功能表征。Dpl1p 结构为人类 SPL 的非常可靠模型提供了基础。上述结果，以及 SPL 突变体的体外和体内研究，揭示了哪些残基参与了活性和底物结合，并为旨在控制这种关键酶活性的研究铺平了道路。
