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首页> 外文期刊>Biochemical Pharmacology >Interaction of the antitumor antibiotic chromomycin A3 with glutathione, a sulfhydryl agent, and the effect upon its DNA binding properties.
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Interaction of the antitumor antibiotic chromomycin A3 with glutathione, a sulfhydryl agent, and the effect upon its DNA binding properties.

机译：抗肿瘤抗生素嗜铬霉素A3与谷胱甘肽，巯基试剂的相互作用及其对DNA结合特性的影响。

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Chromomycin A3 (CHR), an anticancer antibiotic, blocks macromolecular synthesis via reversible interaction with DNA only in the presence of divalent cations like Mg2+. In the absence of DNA, the antibiotic forms a dimer: Mg2+ complex [(CHR)2Mg2+]. It is the DNA-binding ligand. The antibiotic has potential reactive centers that could interact with GSH, the most abundant non-protein thiol in eukaryotic cells and a putative cofactor involved in the activation of many antibiotics in vivo. To understand the mode of action of CHR in vivo, we studied the interactions of CHR and the (CHR)2Mg2+ complex with GSH and the association of the resultant complexes with DNA by means of absorption, fluorescence, and circular dichroism spectroscopy. The novel finding was that GSH interacts non-covalently with CHR without a chemical modification of the antibiotic. The interaction was reversible in nature. The results are reported in two parts: the interaction of CHR with GSH in the absence and presence of Mg2+, and the effect of this interaction on the DNA-binding properties of the antibiotic. CHR forms a single type of complex with GSH. In contrast, (CHR)2Mg2+ forms two different types of complexes with GSH: a low GSH complex at approximately 12 mM GSH and a high GSH complex at > or = 16 mM GSH. Binding and thermodynamic parameters for the reversible association of the complexes with DNA demonstrated that they bind differently to the same DNA. The thermodynamic parameters indicate that the presence of GSH alters the mode of binding of the (CHR)2Mg2+ complex with DNA. The (CHR)2Mg2+ complex binds to DNA via an entropy-driven process, whereas in the presence of GSH the association is enthalpy-driven. The significance of these results in the understanding of the molecular basis of action of the antibiotic is discussed.
机译：铬霉素A3（CHR）是一种抗癌抗生素，仅在二价阳离子（例如Mg2 +）存在时，才通过与DNA的可逆相互作用来阻止大分子合成。在不存在DNA的情况下，抗生素形成二聚体：Mg2 +复合物[（CHR）2Mg2 +]。它是DNA结合配体。该抗生素具有潜在的反应中心，可以与GSH相互作用，GSH是真核细胞中最丰富的非蛋白质硫醇，是一种在体内激活许多抗生素的辅助因子。为了了解CHR在体内的作用方式，我们通过吸收，荧光和圆二色谱法研究了CHR和（CHR）2Mg2 +配合物与GSH的相互作用以及所得配合物与DNA的缔合。新发现是GSH与CHR非共价相互作用，而没有化学修饰抗生素。这种相互作用本质上是可逆的。结果分两部分报道：CHR与GSH在不存在和存在Mg2 +的情况下的相互作用，以及这种相互作用对抗生素的DNA结合特性的影响。 CHR与GSH形成单一类型的复合物。相反，（CHR）2Mg2 +与GSH形成两种不同类型的复合物：大约12 mM GSH处的低GSH复合物和> 16 mM GSH处的高GSH复合物。配合物与DNA可逆结合的结合和热力学参数表明，它们与同一DNA的结合不同。热力学参数表明，GSH的存在改变了（CHR）2Mg2 +复合物与DNA的结合方式。 （CHR）2Mg2 +复合物通过熵驱动的过程与DNA结合，而在GSH的存在下，缔合是焓驱动的。讨论了这些结果对理解抗生素作用的分子基础的意义。

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