Abstract
Chromomycin A3 (CHR, pKa = 7.0), an aureolic acid group of antitumor antibiotic, undergoes self-association in aqueous solution in neutral and anionic forms. Self-association processes of neutral and anionic CHR have been studied in pH 5.0 and pH 9.0, respectively using different spectroscopic methods such as absorbance, fluorescence, CD, NMR and isothermal titration calorimetry (ITC). Results from these studies reveal that at low concentration (2 + CHR (CHR)3 and (CHR)3 + CHR (CHR)4. Analysis of NMR spectra of 100 μM and 1 mM CHR indicates that the self-association of CHR (neutral and anionic form) is most likely to happen via hydrophobic interaction involving the sugar moieties and surrounding water molecules. Calorimetric studies indicate that self-association of both anionic and neutral CHR is entropy driven. These observations imply that sugar substituents play a major role in their state of aggregation after biosynthesis from a gene cluster. The self-association features of the antibiotic have been compared with those of Mithramycin, an antibiotic of the same group.
Highlights
Chromomycin A3 (CHR) is an antitumor antibiotic [1] produced by Streptomyces griseus [2]
We have examined the self-association of CHR in aqueous solution both in neutral and anionic forms by means of spectroscopic and calorimetric (ITC) techniques to characterize the self-association property of CHR and provide a molecular basis of the aggregation
To detect the self-aggregation of neutral and anionic CHR in aqueous buffers of pH 5.0 and pH 9.0 at low concentration range of 1 μM - 7 μM, the fluorescence emission spectra and intensity at peak, 540 nm, were measured as a function of CHR concentration. At this concentration range of CHR there is an increase in the normalized fluorescence spectra in both buffers (Figure 3(a) and Figure 4(a))
Summary
Chromomycin A3 (CHR) is an antitumor antibiotic [1] produced by Streptomyces griseus [2] It belongs to the aureolic acid family of antibiotics. In the presence of bivalent metal ion, like Mg2+, it can bind to minor groove of DNA at GC-rich nucleotide sequence [6] and thereby downregulates the expression of many cancer-related genes that bear GC-rich motifs in their promoter regions, such as the c-myc proto-oncogene [7] Apart from these antitumor activities, CHR acts as a potent inhibitor of neuronal apoptosis induced by oxidative stress and can induce erythroid differentiation of K562 cells by binding to the human γ-globin promoter [8]. CHR has been shown in our laboratory to inhibit the enzyme activity of Zn(II)-containing metalloenzymes [9]
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