Department of Biological Sciences, Texas Tech University, Lubbock, TX, 79409, USA.
Mol Microbiol. 2013 Nov;90(3):489-501. doi: 10.1111/mmi.12378. Epub 2013 Sep 16.
Sphingosine kinase is a key enzyme in sphingolipid metabolism, catalysing the conversion of sphingosine or dihydrosphingosine into sphingosine-1-phosphate or dihydrosphingosine-1-phosphate respectively. In mammals, sphingosine-1-phosphate is a powerful signalling molecule regulating cell growth, differentiation, apoptosis and immunity. Functions of sphingosine kinase or sphingosine-1-phosphate in pathogenic protozoans are virtually unknown. While most organisms possess two closely related sphingosine kinases, only one sphingosine kinase homologue (SKa) can be identified in Leishmania, which are vector-borne protozoan parasites responsible for leishmaniasis. Leishmania SKa is a large, cytoplasmic enzyme capable of phosphorylating both sphingosine and dihydrosphingosine. Remarkably, deletion of SKa leads to catastrophic defects in both the insect stage and mammalian stage of Leishmania parasites. Genetic and biochemical analyses demonstrate that proper expression of SKa is essential for Leishmania parasites to remove toxic metabolites, to survive stressful conditions, and to cause disease in mice. Therefore, SKa is a pleiotropic enzyme with vital roles throughout the life cycle of Leishmania. The essentiality of SKa and its apparent divergence from mammalian counterparts suggests that this enzyme can be selectively targeted to reduce Leishmania infection.
鞘氨醇激酶是鞘脂代谢中的关键酶，催化鞘氨醇或二氢鞘氨醇分别转化为鞘氨醇-1-磷酸或二氢鞘氨醇-1-磷酸。在哺乳动物中，鞘氨醇-1-磷酸是一种强大的信号分子，调节细胞生长、分化、凋亡和免疫。致病原生动物中鞘氨醇激酶或鞘氨醇-1-磷酸的功能几乎未知。虽然大多数生物体都具有两种密切相关的鞘氨醇激酶，但在利什曼原虫中只能鉴定出一种鞘氨醇激酶同源物（SKa），利什曼原虫是一种通过媒介传播的原生动物寄生虫，可导致利什曼病。利什曼原虫 SKa 是一种大型细胞质酶，能够磷酸化鞘氨醇和二氢鞘氨醇。值得注意的是，SKa 的缺失会导致利什曼原虫的昆虫阶段和哺乳动物阶段都出现灾难性缺陷。遗传和生化分析表明，SKa 的正确表达对于利什曼原虫去除有毒代谢物、在应激条件下存活以及在小鼠中引起疾病是必不可少的。因此，SKa 是一种具有重要作用的多功能酶，贯穿利什曼原虫的整个生命周期。SKa 的必需性及其与哺乳动物对应物的明显差异表明，该酶可以被选择性靶向以减少利什曼原虫感染。
