Mahmoudian M, Pakiari A H, Khademi S
Department of Pharmacology, University of Medical Science of Iran, Firoozgar Institute, Tehran.
Biochem Pharmacol. 1992 Jan 22;43(2):283-7. doi: 10.1016/0006-2952(92)90289-u.
Semiemperical quantum chemical calculations have been applied to study the reaction mechanism and mode of inhibition of dihydroorotate dehydrogenase. The structure of substrate, intermediate, product and various inhibitors of dihydroorotate dehydrogenase were optimized using MNDO method and the geometry, heat of formation and the net atomic partial charges of optimized molecules, as well as the energy of the reaction path were calculated. This study shows that the carbanion intermediate of this reaction is rather stable (heat of formation = -134.5 kcal) and readily forms upon nucleophilic attack by groups such as hydroxyl ion. There is good correlation between electronic properties and the biological activities of various inhibitors of this enzyme and the geometry of the most active inhibitor resembles closely that of the intermediate of the reaction. Therefore, it is concluded that the enzymatic oxidation of dihydroorotate dehydrogenase proceeds via formation of an intermediate and the inhibitors bind to the active site of this enzyme in the place of this intermediate.
已应用半经验量子化学计算来研究二氢乳清酸脱氢酶的反应机制和抑制模式。使用MNDO方法优化了二氢乳清酸脱氢酶的底物、中间体、产物和各种抑制剂的结构，并计算了优化分子的几何结构、生成热和净原子电荷以及反应路径的能量。该研究表明，该反应的碳负离子中间体相当稳定（生成热=-134.5千卡），并且在诸如氢氧根离子等基团的亲核攻击下容易形成。该酶的各种抑制剂的电子性质与其生物活性之间存在良好的相关性，并且最具活性的抑制剂的几何结构与反应中间体的几何结构非常相似。因此，可以得出结论，二氢乳清酸脱氢酶的酶促氧化通过中间体的形成进行，并且抑制剂在该中间体的位置与该酶的活性位点结合。
