Association of aureolic acid antibiotic, chromomycin A3 with Cu2+ and its negative effect upon DNA binding property of the antibiotic

作者：Lahiri Shibojyoti; Takao Toshifumi; Devi Pukhrambam Grihanjali; Ghosh Saptaparni; Ghosh Ayanjeet; Dasgupta Amrita; Dasgupta Dipak^*

来源：Biometals, 2012, 25(2): 435-450.

DOI：10.1007/s10534-011-9516-4

• Chromomycin
• Copper ion
• Electrospray ionization mass spectrometry
• Multiple equilibria
• DNA binding
• Distorted octahedral structure

Here we have examined the association of an aureolic acid antibiotic, chromomycin A3 (CHR), with Cu2+. CHR forms a high affinity 2:1 (CHR:Cu2+) complex with dissociation constant of 0.08 x 10(-10) M-2 at 25A degrees C, pH 8.0. The affinity of CHR for Cu2+ is higher than those for Mg2+ and Zn2+ reported earlier from our laboratory. CHR binds preferentially to Cu2+ in presence of equimolar amount of Zn2+. Complex formation between CHR and Cu2+ is an entropy driven endothermic process. Difference between calorimetric and van't Hoff enthalpies indicate the presence of multiple equilibria, supported from biphasic nature of the kinetics of association. Circular dichroism spectroscopy show that [(CHR)(2):Cu2+] complex assumes a structure different from either of the Mg2+ and Zn2+ complex reported earlier. Both [(CHR)(2):Mg2+] and [(CHR)(2):Zn2+] complexes are known to bind DNA. In contrast, [(CHR)(2):Cu2+] complex does not interact with double helical DNA, verified by means of Isothermal Titration Calorimetry of its association with calf thymus DNA and the double stranded decamer (5'-CCGGCGCCGG-3'). In order to interact with double helical DNA, the (antibiotic)(2) : metal (Mg2+ and Zn2+) complexes require a isohelical conformation. Nuclear Magnetic Resonance spectroscopy shows that the Cu2+ complex adopts a distorted octahedral structure, which cannot assume the required conformation to bind to the DNA. This report demonstrates the negative effect of a bivalent metal upon the DNA binding property of CHR, which otherwise binds to DNA in presence of metals like Mg(2+)and Zn2+. The results also indicate that CHR has a potential for chelation therapy in Cu2+ accumulation diseases. However cytotoxicity of the antibiotic might restrict the use.

• 出版日期2012-4