Pulkoski-Gross Michael J, Donaldson Jane C, Obeid Lina M
a Department of Pharmacological Sciences and.
b Department of Medicine , Stony Brook University , Stony Brook , NY , USA .
Crit Rev Biochem Mol Biol. 2015;50(4):298-313. doi: 10.3109/10409238.2015.1039115. Epub 2015 Apr 29.
Sphingolipids represent an important class of bioactive signaling lipids which have key roles in numerous cellular processes. Over the last few decades, the levels of bioactive sphingolipids and/or their metabolizing enzymes have been realized to be important factors involved in disease development and progression, most notably in cancer. Targeting sphingolipid-metabolizing enzymes in disease states has been the focus of many studies and has resulted in a number of pharmacological inhibitors, with some making it into the clinic as therapeutics. In order to better understand the regulation of sphingolipid-metabolizing enzymes as well as to develop much more potent and specific inhibitors, the field of sphingolipids has recently taken a turn toward structural biology. The last decade has seen the structural determination of a number of sphingolipid enzymes and effector proteins. In these terms, one of the most complete arms of the sphingolipid pathway is the sphingosine-1-phosphate (S1P) arm. The structures of proteins involved in the function and regulation of S1P are being used to investigate further the regulation of said proteins as well as in the design and development of inhibitors as potential therapeutics.
鞘脂是一类重要的生物活性信号脂质，在众多细胞过程中发挥关键作用。在过去几十年里，生物活性鞘脂及其代谢酶的水平已被视为疾病发生和发展的重要因素，在癌症中尤为显著。针对疾病状态下的鞘脂代谢酶一直是许多研究的重点，并已产生了多种药理抑制剂，其中一些已进入临床作为治疗药物。为了更好地理解鞘脂代谢酶的调控机制，并开发出更有效、更具特异性的抑制剂，鞘脂领域最近转向了结构生物学。在过去十年中，已经确定了多种鞘脂酶和效应蛋白的结构。就此而言，鞘脂途径中最完整的分支之一是1-磷酸鞘氨醇（S1P）分支。参与S1P功能和调控的蛋白质结构正被用于进一步研究上述蛋白质的调控机制，以及设计和开发作为潜在治疗药物的抑制剂。
