Publication

Article Metrics

Citations


Online attention

Molecular basis of inhibition of Schistosoma japonicum glutathione transferase by ellagic acid: Insights into biophysical and structural studies

DOI: 10.1016/j.molbiopara.2020.111319 DOI Help

Authors: Blessing O. Akumadu (University of the Witwatersrand) , Ramesh Pandian (University of the Witwatersrand) , Jessica Olfsen (University of the Witwatersrand) , Roland Worth (University of the Witwatersrand) , Monare Thulo (University of the Witwatersrand) , Tshireletso Mentor (University of the Witwatersrand) , Sylvia Fanucchi (University of the Witwatersrand) , Yasien Sayed (University of the Witwatersrand) , Heini W. Dirr (University of the Witwatersrand) , Ikechukwu Achilonu (University of the Witwatersrand)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular And Biochemical Parasitology , VOL 240

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 20303

Abstract: Schistosoma japonicum glutathione transferase (Sj26GST), an enzyme central to detoxification of electrophilic compounds in the parasite, is upregulated in response to drug treatment. Therefore, Sj26GST may serve as a potential therapeutic target for the treatment of schistosomiasis. Herewith, we describe the structural basis of inhibition of Sj26GST by ellagic acid (EA). Using 1-chloro-2,4-dinitrobenzene and reduced glutathione (GSH) as Sj26GST substrates, EA was shown to inhibit Sj26GST activity by 66 % with an IC50 of 2.4 μM. Fluorescence spectroscopy showed that EA altered the polarity of the environment of intrinsic tryptophan and that EA decreased (in a dose-dependent manner) the interaction between Sj26GST and 8-Anilino-1-naphthalenesulfonate (ANS), which is a known GST H-site ligand. Thermodynamic studies indicated that the interaction between Sj26GST and EA is spontaneous (ΔG = -29.88 ± 0.07 kJ/mol), enthalpically-driven (ΔH = -9.48 ± 0.42 kJ/mol) with a favourable entropic change (ΔS = 20.40 ± 0.08 kJ/mol/K), and with a stoichiometry of four EA molecules bound per Sj26GST dimer. The 1.53 Å-resolution Sj26GST crystal structure (P 21 21 21 space group) complexed with GSH and EA shows that EA binds primarily at the dimer interface, stabilised largely by Van der Waal forces and H-bonding. Besides, EA bound near the H-site and less than 3.5 Å from the ε-NH2 of the γ-glutamyl moiety of GSH, in each subunit.

Journal Keywords: Sj26GST; GST; Ellagic acid; Inhibition; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography