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  • Heparin and suramin are highly


    Heparin and suramin are highly negatively charged molecules, and they are in this aspect, similar to DNA and likely to compete with DNA by binding to the protein cationic groups [17] (Fig. 1). The inhibitory effect of heparin and suramin on DNA and RNA binding proteins has been described [[18], [19], [20]]. Heparin, a linear and polydisperse polysaccharide, consists of repeating units of 1 → 4 linked pyranosyluronic 535 2 and 2‑amino‑2‑deoxyglucopyranose (glucosamine) residues [21] and an acetyl or sulfo group can substitute the glucosamine amino group. The glucosamine residues at position 3 and 6 can be either substituted with an O‑sulfo group or un-substituted. The uronic acid, which can be l‑iduronic or d‑glucuronic acid, may also contain a 2‑O‑sulfo group. The negative charges per disaccharide in heparin is averaged, 2.7 [22] and, consequently, the characteristic binding sites for heparin are clusters of positively charged basic amino acids forming ion pairs with spatially defined negatively charged sulfo or carboxyl groups of heparin. Suramin (SUV) (developed within the Bayer AG in 1916), a drug that has been used extensively in humans to treat trypanosomiasis [23], and onchocerciasis, [24]. SUV is a symmetric polyanion, containing two naphthalene-trisulfonic acid head groups [25] and six sulfonate groups, which are responsible for the strong negative charge of the molecule. DNA repair proteins are interesting drug targets as the inactivation or inhibition of the human MutY homolog leads to tumorigenic mutations and, to the elevation of genomic 8-oxo-G levels. The disruption of the MutY function is profoundly mutagenic to transformed human cells [23] and based on this observation, it is probable that the inhibition of the Cp-MutY activity results in severe damage to the pathogen. The purpose of this study was to characterize the interaction of free adenine with the MutY protein from C. pseudotuberculosis and to characterize it competitive binding with the two polyanions heparin and SUV.
    Material and methods
    Results and discussion
    Conclusion DNA repair mechanisms in C. pseudotuberculosis remain poorly understood and research in this area can contribute to narrow the search for molecular targets against caseous lymphadenitis. The involvement of Cp-MutY in DNA repair and prevention of mutations was demonstrated [35]. Furthermore, in silico analyses of DNA repair pathways of 15 Corynebacterium species, including C. pseudotuberculosis demonstrated, that genes involved in oxidative damage repair, are highly conserved, being present in all investigated species. This suggests that repair of oxidative lesions is essential to ensure genomic stability and survival of these organisms [56]. The inhibition of these repair mechanisms will affect the viability of the pathogen. Our results demonstrate the competition of adenine and heparin about the same binding region in Cp-MutY. Crystallographic and inhibitory studies have demonstrated that free adenine binds to the active site pocket of MutY proteins. The interaction of heparin and suramin at the adenine binding site has an effect on the subsequent binding of adenine. The determination of Kd values for adenine, heparin and suramin interactions with Cp-MutY showed a stronger affinity of the polyanions when compared with adenine, indicating the potential of this molecules to serve as lead molecules to generate potential inhibitors for MutY proteins. Further research is warranted to decipher the binding, inhibition and drugability of heparin and suramin to combat C. pseudotuberculosis bacteria.
    Conflict of interest
    Introduction The integrity and accuracy of genome are critical to all organisms [1], [2]. However, many environmental factors in daily life can cause irreversible damage to DNA, such as radiation and toxic chemicals [3], [4]. dU damage is a commonly found damage which may be caused by deamination of cytosine or the misincorporation during DNA replication. If not repaired, it may lead to permanent gene mutations [5], [6]. Uracil-DNA glycosylase (UDG) is an indispensable DNA damage repair enzyme in uracil-induced lesions, which can flip uracil out of DNA backbone by catalyzing the break of N-glycosidic bond between uracil and deoxyribose sugar, exposing an apurinic/apyrimidinic (AP) site. Then by coupling with other repair enzymes, the DNA repair can be realized [7], [8]. However, aberrant UDG levels are sometimes closely associated with many diseases, such as human immunodeficiency, bloom syndrome, lymphoma and cancers [9], [10], [11], [12]. Therefore, the development of sensitive methods for detecting UDG activity is very necessary for both fundamental biological research and drug discovery.