Plasmodium falciparum dUTPase:: Studies on protein stability and binding of deoxyuridine derivatives

被引:12
|
作者
Quesada-Soriano, Indalecio
Alexander Musso-Buendia, Juan
Tellez-Sanz, Ramiro
Miguel Ruiz-Perez, Luis
Baron, Carmen
Gonzalez-Pacanowska, Dolores
Garcia-Fuentes, Luis
机构
[1] Univ Almeria, Fac Ciencias Expt, Dipartimento Quim Fis Bioquim & Q Inorgan, Almeria 04120, Spain
[2] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain
来源
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS | 2007年 / 1774卷 / 07期
关键词
calorimetry; dUTPase; Plasmodium falciparum; thermal denaturation; binding;
D O I
10.1016/j.bbapap.2007.04.013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Deoxyuridine triphosphate nucleotidohydrolase (dUTPase), a ubiquitous enzyme preventing a deleterious incorporation of uracil into DNA, has been thought of as a novel target for anticancer and antiviral drug design. The interaction of Plasmodium falciparum dUTPase (PfdUTPase) with deoxyuridine derivatives (dU, dUMP, dUDP and dUpNHpp) has been studied thermodynamically by both isothermal titration and differential scanning calorimetry. ITC shows no cooperativity for the binding of these derivatives. Dependencies in the binding thermodynamic parameters (enthalpy, entropy and Gibbs energy changes) with the number of phosphate groups in the nucleotide are obtained, and from the heat capacity changes no significant conformational changes upon binding are inferred. DSC shows PfdUTPase trimer is very stable but denatures irreversibly, with a more complex denaturation profile than other homologous trimeric dUTPases. The presence of magnesium ions does not influence the denaturation profile, while the presence of deoxyuridine derivatives increases the stability. The increase depends upon nucleotide concentration and type, with dUDP having the greater effect. (c) 2007 Elsevier B.V. All rights reserved.
引用
收藏
页码:936 / 945
页数:10
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