Inhibitory action of polyunsaturated fatty acids on IMP dehydrogenase
Inhibitory action of polyunsaturated fatty acids on IMP dehydrogenase
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DOI：
10.1016/j.biochi.2007.01.009
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发表时间：
2007-05-01
期刊：
影响因子：
3.9
通讯作者：
Kato, Norihisa
中科院分区：
文献类型：
--
作者：
Mizushina, Yoshiyuki;Dairaku, Issei;Kato, Norihisa
我们从天然化合物中筛选出小鼠肌苷单磷酸脱氢酶(IMPDH)的抑制剂，发现一种脂肪酸亚油酸(C18：2)能抑制IMPDH的活性。在C18：2脂肪酸衍生物中，亚油酸的所有反式构型(即亚麻酸)、酯形式、醇形式和羟基的添加对抑制活性没有影响。因此，含有顺式脂肪酸双键的羧酸和烷基链的两个部分可能对抑制作用是必不可少的。在所考察的各种碳原子长度和脂肪酸的双键中，C20：2-脂肪酸的抑制作用最强，当浓度为16.1 mU时，抑制作用为50%。二十碳二烯酸对IMPDH活性有抑制作用，且与IMP呈竞争性(K-I=3.1mM)。C20-脂肪酸的抑制作用顺序为：C20：2>；C20：3>；C20：1>；C20：4>；C20：5；C20：0无抑制作用。计算了直链C20-脂肪酸的能量最小化三维结构，发现脂肪酸分子结构中20.7-22.5埃的长度和4.7-7.2埃的宽度是抑制IMPDH的重要因素。进行了C20-脂肪酸与小鼠IMPDHⅡ(PDB代码：1NF7)的对接模拟，发现C20-脂肪酸能与IMP竞争性结合活性部位的氨基酸残基Cys331。在此基础上，对脂肪酸抑制IMPDH的机制进行了探讨。(C)2007年爱思唯尔·马森公司。版权所有。
We screened the inhibitor of mouse inosine 5 '-monophosphate dehydrogenase (IMPDH) type II from natural compounds, and found that a fatty acid, linoleic acid (C18:2), inhibited IMPDH activity. In the C18:2 fatty acid derivatives, all trans-configuration (i.e., linoelaidic acid), ester form, alcohol form, and addition of the hydroxyl group of linoleic acid had no effect on inhibitory activity. Therefore, both parts of a carboxylic acid and an alkyl chain containing cis-type double bonds of fatty acid might be essential for inhibition. Among the various carbon atom lengths and double bonds of fatty acids examined, the strongest inhibitor was C20:2-fatty acid, eicosadienoic acid, and 50% inhibition was observed at a concentration of 16.1 mu M. Eicosadienoic acid induced the inhibition of IMPDH activity and was competitive with respect to IMP (K-i = 3.1 mu M). For inhibitory effect, the C20-fatty acids ranked as follows: C20:2 > C20:3 > C20:1 > > C20:4 > C20:5, and C20:0 showed no inhibition. The energy-minimized three-dimensional structures of linear-chain C20-fatty acids were calculated, and it was found that a length of 20.7-22.5 angstrom and width of 4.7-7.2 angstrom in the fatty acid molecular structure was suggested to be important for IMPDH inhibition. Docking simulation of C20-fatty acids and mouse IMPDH type II, which was homology modeled from human IMPDH type II (PDB code: 1NF7), was performed, and the fatty acid could bind to Cys331, which is a amino acid residue of the active site, competitively with IMP. Based on these results, the IMPDH-inhibitory mechanism of fatty acids is discussed. (C) 2007 Elsevier Masson SAS. All rights reserved.