人类和老鼠dihydroorotate脱氢酶的抑制作用动力学atovaquone, lawsone衍生品,brequinar钠和polyporic酸。

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Knecht W, hensel J, Loffler M

人类和老鼠dihydroorotate脱氢酶的抑制作用动力学atovaquone, lawsone衍生品,brequinar钠和polyporic酸。

化学生物相互作用。2000年1月3;124 (1):61 - 76。

PubMed ID

10658902 (在PubMed

]

文摘

Mitochondrially-bound dihydroorotate脱氢酶(EC 1.3.99.11)催化第四顺序一步一磷酸尿苷的从头合成。酶已被确认为或猜测是药理isoxazol的目标,三嗪,cinchoninic酸和(naphtho)醌衍生品施加抗增殖、免疫抑制、抗寄生虫的影响。尽管如此广泛的生物和临床相关性,没有比较研究drug-dihydroorotate脱氢酶相互作用。在这里,我们描述一个研究抑制的纯化重组人类和老鼠dihydroorotate脱氢酶由十个化合物。1 4-Naphthoquinone 5、8-hydroxy-naphthoquinone和天然化合物juglon plumbagin polyporic酸(醌衍生物)被发现函数作为替代电子受体控制酶活性的10 - 30%。人类和老鼠酶活性下降了50%的天然化合物lawsone(分别为> 500和49 microM)和衍生品dichloroally-lawsone(67海里),拉帕醇(618和61 nM)和atovaquone (15 microM和698海里)。对醌co-substrate dihydroorotate脱氢酶,atovaquone (Kic = 2.7 microM)和dichloroally-lawsone (Kic = 9.8海里)被证明是人类dihydroorotate脱氢酶的竞争性抑制剂。Atovaquone (Kic = 60海里)也具有竞争力鼠酶的抑制剂。Dichloroally] -lawsone被发现是一个依赖于时间的老鼠酶的抑制剂,最低的抑制常数(Ki * = 0.77海里)确定到目前为止对哺乳动物dihydroorotate脱氢酶。以前曾有报道称是另一种抑制剂,brequinar slow-binding人类dihydroorotate脱氢酶的抑制剂(W。 Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%.

DrugBank数据引用了这篇文章

药物靶点

药物	目标	类	生物	药理作用	行动
Atovaquone	Dihydroorotate脱氢酶(醌),线粒体	蛋白质	人类	未知的	抑制剂	细节