MECHANISM OF THE INHIBITION OF CHOLESTEROL-BIOSYNTHESIS BY 6-FLUOROMEVALONATE
MECHANISM OF THE INHIBITION OF CHOLESTEROL-BIOSYNTHESIS BY 6-FLUOROMEVALONATE
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DOI：
10.1042/bj2270247
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发表时间：
1985-01-01
影响因子：
4.1
通讯作者：
JUNG, MJ
中科院分区：
文献类型：
--
作者：
NAVE, JF;DORCHYMONT, H;JUNG, MJ
6-Fluoromevalonate 可阻止甲羟戊酸（而非异戊烯基焦磷酸盐）掺入大鼠肝脏多酶系统中的非皂化脂质中。使用3H标记的6-氟甲羟戊酸，发现6-氟甲羟戊酸在该系统中转化为其磷酸和焦磷酸衍生物。研究了两种激酶的动力学。 6-Fluoromevalonate 5-焦磷酸是焦磷酸甲羟戊酸脱羧酶的有效竞争性抑制剂 (K1 = 37 nM)。在胆固醇生物合成的多酶测定中，在5μM-6-氟甲羟戊酸存在下，甲羟戊酸5-磷酸和甲羟戊酸5-焦磷酸积累，并且6-氟甲羟戊酸5-焦磷酸在抑制胆固醇生物合成方面比6-氟甲羟戊酸更有效。 6-氟甲羟戊酸在焦磷酸化后在焦磷酸甲羟戊酸脱羧酶水平上阻断胆固醇生物合成。 [高胆固醇血症是冠状动脉疾病的主要危险因素]。
6-Fluoromevalonate blocks the incorporation of mevalonic acid, but not that of isopentenyl pyrophosphate, into non-saponifiable lipids in a rat liver multienzyme system. With 3H-labeled 6-fluoromevalonate, it was found that 6-fluoromevalonate is converted to its phospho and pyrophospho derivatives in this system. The kinetics of the 2 kinases were studied. 6-Fluoromevalonate 5-pyrophosphate is a potent competitive inhibitor of pyrophosphomevalonate decarboxylase (K1 = 37 nM). In the multienzyme assay for cholesterol biosynthesis, there is accumulation of mevalonate 5-phosphate and mevalonate 5-pyrophosphate in the presence of 5 .mu.M-6-fluoromevalonate, and 6-fluoromevalonate 5-pyrophosphate is more effective than 6-fluoromevalonate in inhibiting cholesterol biosynthesis. 6-Fluoromevalonate blocks cholesterol biosynthesis at the level of pyrophosphomevalonate decarboxylase after being pyrophosphorylated. [Hypercholesterolemia is a major risk factor in coronary artery disease.].