Vunnam R R, Radin N S
Chem Phys Lipids. 1980 Apr;26(3):265-78. doi: 10.1016/0009-3084(80)90057-2.
In a search for potent inhibitors of glucocerebroside biosynthesis, we synthesized aromatic analogs of the enzyme's substrate, ceramide, many of which have not previously been described in the literature. Mouse brain and spleen, rat brain, and human placenta and spleen were all found to be susceptible to inhibition by a variety of compounds, although to differing extents. The most potent inhibitor was 2-decanoylamino-3-morpholino-1-phenylpropanol. The dehydro version of this compound (2-decanoylamino-3-morpholinopropiophenone) was less effective but it produced inactivation of the enzyme, probably by covalent reaction with the enzyme's active site. Examination of the various effects seen leads us to suggest that the active region of the enzyme contains four recognitional sites: an anionic moiety that may bind the glucose in activated form, an oxygen-binding region oriented toward the third carbon atom of ceramide, a narrow region that binds the alkyl chain of the fatty acid moiety, and a less narrow region that binds the hydrocarbon chain of the sphingoid base moiety.
为了寻找有效的葡糖脑苷脂生物合成抑制剂，我们合成了该酶底物神经酰胺的芳香类似物，其中许多此前尚未见文献报道。结果发现，小鼠脑和脾脏、大鼠脑以及人胎盘和脾脏均对多种化合物的抑制作用敏感，不过程度有所不同。最有效的抑制剂是2-癸酰氨基-3-吗啉代-1-苯基丙醇。该化合物的脱氢形式（2-癸酰氨基-3-吗啉代苯丙酮）效果稍差，但可能通过与酶的活性位点发生共价反应使酶失活。对所观察到的各种效应进行研究后，我们认为该酶的活性区域包含四个识别位点：一个可能结合活化形式葡萄糖的阴离子部分、一个朝向神经酰胺第三个碳原子的氧结合区域、一个结合脂肪酸部分烷基链的狭窄区域以及一个结合鞘氨醇碱部分烃链的稍宽区域。
