Li Bing-Hui, Ma Xiao-Feng, Wang Yan, Tian Wei-Xi
Department of Biology, Graduate University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
J Biochem. 2005 Dec;138(6):679-85. doi: 10.1093/jb/mvi171.
Many flavone derivatives inhibit FAS, and their A and B rings play an important role, but is the C ring necessary for the inhibition of FAS? Here, using nordihydroguaiaretic acid (NDGA), with two phenyl rings connected by a four-carbon chain, as a representative, the structural basis for the inhibition of animal fatty acid synthase (FAS) by polyphenols was investigated. NDGA potently inhibits the overall reaction of FAS (IC(50) = 9.3 +/- 0.1 muM). The kinetic study indicated that NDGA inhibits FAS competitively with respect to acetyl-CoA, noncompetitively with respect to malonyl-CoA, and in a mixed manner with respect to NADPH. The inhibitory mechanism is the same as that of FAS flavonoid inhibitors. This suggests that the C ring of flavonoids is not essential for their FAS inhibitory effect. This conclusion was further confirmed by the results obtained for different polyphenols. A structure-activity relationship study indicated that a biphenyl core exists in all FAS polyphenol inhibitors. Thus, we propose a common model possibly shared by all FAS polyphenol inhibitors. The model includes two almost planar aromatic rings with their respective hydroxyl groups, and a proper ester linkage between the two rings that possibly causes the inhibition of FAS by irreversibly inhibiting the beta-ketoacyl reductase domain.
许多黄酮衍生物可抑制脂肪酸合酶（FAS），其A环和B环发挥着重要作用，但C环对于抑制FAS是否必要呢？在此，以通过四碳链连接两个苯环的去甲二氢愈创木酸（NDGA）为代表，研究了多酚抑制动物脂肪酸合酶（FAS）的结构基础。NDGA能有效抑制FAS的整体反应（IC(50)=9.3±0.1μM）。动力学研究表明，NDGA对乙酰辅酶A呈竞争性抑制FAS，对丙二酰辅酶A呈非竞争性抑制，对NADPH呈混合型抑制。其抑制机制与FAS类黄酮抑制剂相同。这表明黄酮类化合物的C环对其FAS抑制作用并非必不可少。不同多酚的研究结果进一步证实了这一结论。构效关系研究表明，所有FAS多酚抑制剂中均存在联苯核心。因此，我们提出了一个所有FAS多酚抑制剂可能共有的通用模型。该模型包括两个各自带有羟基的近乎平面的芳香环，以及两个环之间适当的酯键，这可能通过不可逆地抑制β-酮酰基还原酶结构域而导致对FAS的抑制。
