The antiproliferative activity of di-2-pyridylketone dithiocarbamate is partly attributed to catalase inhibition: detailing the interaction by spectroscopic methods†

IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology
Cuiping Li, Youxun Liu, Yun Fu, Tengfei Huang, Lixia Kang and Changzheng Li
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引用次数: 8

Abstract

The bioactivity of drugs is attributed to their interaction with biological molecules, embodied in either their direct or indirect influence on enzyme activity and conformation. Di-2-pyridylketone hydrazine dithiocarbamate (DpdtC) exhibits significant antitumor activity in our preliminary study. We speculated that its activity may partly stem from enzyme inhibition due to strong metal chelating ability. To this end, we assessed its effect on catalase from erythrocytes and found evidence of inhibition, which was further confirmed by ROS determination in vivo. Thus, detailing the interaction between the agent and catalase via spectroscopic methods and molecular docking was required to obtain information on both the dynamics and thermodynamic parameters. The Lineweaver–Burk plot implied an uncompetitive pattern between DpdtC and catalase from beef liver, and IC50 = ~7 μM. The thermodynamic parameters from fluorescence quenching measurements indicated that DpdtC could bind to catalase with moderate affinity (Ka = approximately 104 M?1). CD spectra revealed that DpdtC could significantly disrupt the secondary structure of catalase. Docking studies indicated that DpdtC bound to a flexible region of catalase, involving hydrogen bonds and salt bond; this was consistent with thermodynamic results from spectral investigations. Our data clearly showed that catalase inhibition of DpdtC was not due to direct chelation of iron from heme (killing), but through an allosteric effect. Thus, it can be concluded that the antiproliferative activity of DpdtC is partially attributed to its catalase inhibition.

Abstract Image

二-2-吡啶基酮二硫代氨基甲酸酯的抗增殖活性部分归因于过氧化氢酶的抑制作用:通过光谱方法详细描述相互作用†
药物的生物活性归因于它们与生物分子的相互作用,具体表现为它们对酶活性和构象的直接或间接影响。二-2-吡啶基酮肼二硫代氨基甲酸酯(DpdtC)在我们的初步研究中显示出显著的抗肿瘤活性。我们推测其活性可能部分源于其较强的金属螯合能力对酶的抑制作用。为此,我们评估了其对红细胞过氧化氢酶的影响,发现了抑制的证据,并通过体内ROS测定进一步证实了这一点。因此,需要通过光谱方法和分子对接来详细描述该试剂与过氧化氢酶之间的相互作用,以获得动力学和热力学参数的信息。Lineweaver-Burk图显示DpdtC与牛肝过氧化氢酶呈非竞争模式,IC50 = ~7 μM。荧光猝灭测量的热力学参数表明,DpdtC与过氧化氢酶的结合具有中等亲和力(Ka =约104 M?1)。CD谱显示,DpdtC能显著破坏过氧化氢酶的二级结构。对接研究表明,DpdtC与过氧化氢酶的柔性区域结合,涉及氢键和盐键;这与光谱研究的热力学结果是一致的。我们的数据清楚地表明,过氧化氢酶对DpdtC的抑制不是由于铁与血红素的直接螯合(杀死),而是通过变构效应。因此,可以得出结论,ddptc的抗增殖活性部分归因于其过氧化氢酶抑制作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular BioSystems
Molecular BioSystems 生物-生化与分子生物学
CiteScore
2.94
自引率
0.00%
发文量
0
审稿时长
2.6 months
期刊介绍: Molecular Omics publishes molecular level experimental and bioinformatics research in the -omics sciences, including genomics, proteomics, transcriptomics and metabolomics. We will also welcome multidisciplinary papers presenting studies combining different types of omics, or the interface of omics and other fields such as systems biology or chemical biology.
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