Yeang Calvin, Varshney Shweta, Wang Renxiao, Zhang Ya, Ye Deyong, Jiang Xian-Cheng
Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, USA.
Biochim Biophys Acta. 2008 Oct;1781(10):610-7. doi: 10.1016/j.bbalip.2008.07.002. Epub 2008 Jul 23.
Sphingomyelin synthase (SMS) sits at the crossroads of sphingomyelin (SM), ceramide, diacylglycerol (DAG) metabolism. It utilizes ceramide and phosphatidylcholine as substrates to produce SM and DAG, thereby regulating lipid messengers which play a role in cell survival and apoptosis. There are two isoforms of the enzyme, SMS1 and SMS2. Both SMS1 and SMS2 contain two histidines and one aspartic acid which are evolutionary conserved within the lipid phosphate phosphatase superfamily. In this study, we systematically mutated these amino acids using site-directed mutagenesis and found that each point mutation abolished SMS activity without altering cellular distribution. We also explored the domains which are responsible for cellular distribution of both enzymes. Given their role as a potential regulator of diseases, these findings, coupled with homology modeling of SMS1 and SMS2, will be useful for drug development targeting SMS.
鞘磷脂合酶（SMS）处于鞘磷脂（SM）、神经酰胺、二酰基甘油（DAG）代谢的交叉点。它利用神经酰胺和磷脂酰胆碱作为底物来生成SM和DAG，从而调节在细胞存活和凋亡中起作用的脂质信使。该酶有两种亚型，即SMS1和SMS2。SMS1和SMS2都含有两个组氨酸和一个天冬氨酸，它们在脂质磷酸磷酸酶超家族中是进化保守的。在本研究中，我们使用定点诱变系统地突变了这些氨基酸，发现每个点突变都消除了SMS活性，而不改变细胞分布。我们还探索了负责这两种酶细胞分布的结构域。鉴于它们作为疾病潜在调节因子的作用，这些发现，再加上SMS1和SMS2的同源建模，将有助于针对SMS的药物开发。
