Shukla G S, Shukla A, Radin N S
Mental Health Research Institute, University of Michigan, Ann Arbor.
J Neurochem. 1991 Jun;56(6):2125-32. doi: 10.1111/j.1471-4159.1991.tb03475.x.
Gangliosides stimulate the hydrolysis of glucosylceramide (GlcCer), their precursor, and therefore may lower the level of cellular GlcCer and exert a feedback control effect to slow the formation of gangliosides. Tests were made to see if a similar effect on GlcCer levels can be exerted by the action of gangliosides on GlcCer synthesis. Using a new assay procedure, we showed that gangliosides do inhibit the synthase in brain membranes quite effectively, the most active being those lipids with more sugar and sialic acid moieties. Mice injected with a mixture of brain gangliosides for 5 days were found to have a lower level of ceramide:UDP-Glc glucosyltransferase activity in brain, liver, and kidney. The inhibition seems to be exerted by competition for the active site and binding to effector site(s) on the enzyme. It is possible that the reported therapeutic actions of gangliosides on the nervous system are, in part, the result of lowered levels of GlcCer. Malignant tumors shed gangliosides into the extracellular fluid, which are believed to block the generation of antibodies by the host's immunodefense system; this effect also may be due, in part, to reduction in the GlcCer level of immunogenic cells. A new finding is that a ceramide containing phytosphingosine is a markedly better substrate for GlcCer synthase than one containing the more common base.
神经节苷脂可刺激其前体糖基神经酰胺（GlcCer）的水解，因此可能会降低细胞内GlcCer的水平，并发挥反馈控制作用以减缓神经节苷脂的形成。我们进行了测试，以观察神经节苷脂对GlcCer合成的作用是否能对GlcCer水平产生类似影响。使用一种新的检测方法，我们发现神经节苷脂确实能非常有效地抑制脑膜中的合成酶，其中活性最高的是那些含有更多糖和唾液酸部分的脂质。给小鼠注射脑源性神经节苷脂混合物5天后，发现其脑、肝和肾中的神经酰胺：UDP - Glc糖基转移酶活性较低。这种抑制作用似乎是通过竞争活性位点以及与酶上的效应位点结合来实现的。神经节苷脂对神经系统的治疗作用可能部分是由于GlcCer水平降低所致。恶性肿瘤会将神经节苷脂释放到细胞外液中，据信这会阻碍宿主免疫防御系统产生抗体；这种作用也可能部分归因于免疫原性细胞中GlcCer水平的降低。一项新发现是，含有植物鞘氨醇的神经酰胺作为GlcCer合成酶的底物，比含有更常见碱基的神经酰胺明显更好。
