In vitro studies in a myelogenous leukemia cell line suggest an organized binding of geranylgeranyl diphosphate synthase inhibitors.
In vitro studies in a myelogenous leukemia cell line suggest an organized binding of geranylgeranyl diphosphate synthase inhibitors.
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DOI：
10.1016/j.bcp.2015.04.009
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发表时间：
2015-07-15
影响因子：
5.8
通讯作者：
Hohl RJ
中科院分区：
文献类型：
--
作者：
Reilly JE;Zhou X;Tong H;Kuder CH;Wiemer DF;Hohl RJ
在K562慢性髓性白血病细胞系中测试了一小组类异戊二烯双磷酸盐醚，以确定它们对类异戊二烯生物合成的影响。其中5种化合物对香叶基二磷酸合成酶（GGDPS）的抑制作用IC50值小于1 μM，但在细胞内的表观活性差异较大。特别是，c -香叶基- o -戊烯基和c -戊烯基- o -香叶基双膦酸酯的活性有很大不同，前者在细胞中始终表现出更大的香叶基基酰化损伤，而后者在GGDPS酶分析中表现出更大的影响。总之，这些发现表明这些抑制剂在香叶基二磷酸合酶的两个疏水通道中有组织地结合。
A small set of isoprenoid bisphosphonates ethers have been tested in the K562 chronic myelogenous leukemia cell line to determine their impact on isoprenoid biosynthesis. Five of these compounds inhibit geranylgeranyl diphosphate synthase (GGDPS) with IC50 values below 1 μM in enzyme assays, but in cells their apparent activity is more varied. In particular, the isomeric C-geranyl-O-prenyl and C-prenyl-O-geranyl bisphosphonates are quite different in their activity with the former consistently demonstrating greater impairment of geranylgeranylation in cells but the latter showing greater impact in the enzyme assays with GGDPS. Together, these findings suggest an organized binding of these inhibitors in the two hydrophobic channels of the geranylgeranyl diphosphate synthase enzyme.