Gangliosides inhibit glucosylceramide synthase: a possible role in ganglioside therapy.
Gangliosides inhibit glucosylceramide synthase: a possible role in ganglioside therapy.
复制标题
神经节苷脂抑制葡萄糖神经酰胺合酶：神经节苷脂治疗中的可能作用。
DOI：
10.1111/j.1471-4159.1991.tb03475.x
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发表时间：
1991
影响因子：
4.7
通讯作者：
Radin,NS
中科院分区：
文献类型：
--
作者：
Shukla,GS;Shukla,A;Radin,NS
神经节苷脂刺激其前体葡萄糖神经酰胺（GlcCer）的水解，因此可能降低细胞GlcCer的水平，并发挥反馈控制作用以减缓神经节苷脂的形成。进行测试以观察神经节苷脂对GlcCer合成的作用是否可以对GlcCer水平产生类似的影响。使用一种新的检测方法，我们发现神经节苷脂确实能有效地抑制脑细胞膜中的合成酶，最活跃的是那些含有更多糖和唾液酸部分的脂质。注射脑神经节苷脂混合物5天的小鼠发现脑、肝和肾中神经酰胺：UDP-Glc葡萄糖基转移酶活性水平较低。抑制作用似乎是通过竞争活性位点和结合酶上的效应位点来实现的。神经节苷脂对神经系统的治疗作用可能部分是GlcCer水平降低的结果。恶性肿瘤将神经节苷脂脱落到细胞外液中，据信其阻断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的GlcCer水平降低。一个新的发现是，含有神经酰胺的植物鞘氨醇是一个明显更好的底物GlcCer合酶比一个含有更常见的碱。
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 glucosyl‐transferase 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.