6-氟甲羟戊酸抑制胆固醇生物合成的机制
Mechanism of the inhibition of cholesterol biosynthesis by 6-fluoromevalonate.
作者信息
Nave J F, d'Orchymont H, Ducep J B, Piriou F, Jung M J
出版信息
Biochem J. 1985 Apr 1;227(1):247-54. doi: 10.1042/bj2270247.
Abstract
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-labelled 6-fluoromevalonate, it was found that 6-fluoromevalonate is converted to its phospho and pyrophospho derivatives in this system. The kinetics of the two kinases were studied. 6-Fluoromevalonate 5-pyrophosphate is a potent competitive inhibitor of pyrophosphomevalonate decarboxylase (Ki 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 microM-6-fluoromevalonate, and 6-fluoromevalonate 5-pyrophosphate is more effective than 6-fluoromevalonate in inhibiting cholesterol biosynthesis. We suggest therefore that 6-fluoromevalonate blocks cholesterol biosynthesis at the level of pyrophosphomevalonate decarboxylase after being pyrophosphorylated.
摘要
6-氟甲羟戊酸可阻断甲羟戊酸而非异戊烯基焦磷酸掺入大鼠肝脏多酶系统中的非皂化脂质。利用3H标记的6-氟甲羟戊酸，发现在该系统中6-氟甲羟戊酸可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-氟甲羟戊酸5-焦磷酸是焦磷酸甲羟戊酸脱羧酶的强效竞争性抑制剂（Ki为37 nM）。在胆固醇生物合成的多酶测定中，在存在5 microM - 6-氟甲羟戊酸的情况下，甲羟戊酸5-磷酸和甲羟戊酸5-焦磷酸会积累，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。因此我们认为，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阻断胆固醇生物合成。
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