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

Akumadu, Blessing Oluebube; Pandian, Ramesh; Olfsen, Jessica; Worth, Roland; Thulo, Monare; Mentor, Tshireletso; Fanucchi, Sylvia; Sayed, Yasien; Dirr, Heini W.; Achilonu, Ikechukwu

doi:10.1016/j.molbiopara.2020.111319

Cited by 13 publications

(13 citation statements)

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“…The reference structure, the crystal structure of glutathione S-transferase from Schistosoma japonicum (PDB ID: 6RWD) [ 17 ], was recovered from the RCSB PDB and utilized to generate a Sbh26GST homology model using the SWISS-model online homology modelling tool [ 28 ]. Models were validated by PROCHECK [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

“…Some studies indicate that known inhibitors of human GSTs, such as ethacrynic acid, usually binds at the H-site. However, in schistosomes, some inhibitors, such as ellagic acid, bind both the H-site and dimer interface of Sj26GST [ 17 ], while others, such as BSP, favor binding the dimer interface of Sj26GST [ 18 ]. This knowledge provides an alternative site for non-substrate xenobiotics to regulate GSTs.…”

Section: Introductionmentioning

confidence: 99%

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Engineering a Pseudo-26-kDa Schistosoma Glutathione Transferase from bovis/haematobium for Structure, Kinetics, and Ligandin Studies

et al. 2021

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Glutathione transferases (GSTs) are the main detoxification enzymes in schistosomes. These parasitic enzymes tend to be upregulated during drug treatment, with Schistosoma haematobium being one of the species that mainly affect humans. There is a lack of complete sequence information on the closely related bovis and haematobium 26-kDa GST isoforms in any database. Consequently, we engineered a pseudo-26-kDa S. bovis/haematobium GST (Sbh26GST) to understand structure–function relations and ligandin activity towards selected potential ligands. Sbh26GST was overexpressed in Escherichia coli as an MBP-fusion protein, purified to homogeneity and catalyzed 1-chloro-2,4-dinitrobenzene-glutathione (CDNB-GSH) conjugation activity, with a specific activity of 13 μmol/min/mg. This activity decreased by ~95% in the presence of bromosulfophthalein (BSP), which showed an IC50 of 27 µM. Additionally, enzyme kinetics revealed that BSP acts as a non-competitive inhibitor relative to GSH. Spectroscopic studies affirmed that Sbh26GST adopts the canonical GST structure, which is predominantly α-helical. Further extrinsic 8-anilino-1-naphthalenesulfonate (ANS) spectroscopy illustrated that BSP, praziquantel (PZQ), and artemisinin (ART) might preferentially bind at the dimer interface or in proximity to the hydrophobic substrate-binding site of the enzyme. The Sbh26GST-BSP interaction is both enthalpically and entropically driven, with a stoichiometry of one BSP molecule per Sbh26GST dimer. Enzyme stability appeared enhanced in the presence of BSP and GSH. Induced fit ligand docking affirmed the spectroscopic, thermodynamic, and molecular modelling results. In conclusion, BSP is a potent inhibitor of Sbh26GST and could potentially be rationalized as a treatment for schistosomiasis.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Engineering a Pseudo-26-kDa Schistosoma Glutathione Transferase from bovis/haematobium for Structure, Kinetics, and Ligandin Studies

et al. 2021

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“…These results might be attributed to the formation of a relatively stable pyridine ring with both carbonyl and amino groups on the ARP molecule participating in the reaction (Figure b), as thus, the polyhydroxyl structure of the xylose moiety could be available for interactions with the hydroxyl groups via hydrogen bonding . On the other hand, the amino acid moiety of the ARP could also show a high binding affinity with ellagic acid via hydrogen-bonds at diverse sites, which greatly improved the reactivity of ellagic acid trapping the ARP during the Maillard reaction. , …”

Section: Resultsmentioning

confidence: 99%

Maillard Browning Inhibition by Ellagic Acid via Its Adduct Formation with the Amadori Rearrangement Product

Cui

Wang

Hayat

et al. 2021

J. Agric. Food Chem.

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The Maillard reaction performed under a stepwise increase of temperature was applied for researching the inhibition of Maillard browning caused by ellagic acid. Ellagic acid was found effective for the inhibition of melanoidin formation in the xylose− glycine Maillard reaction but depended on its dosage and the point of time it was added in the reaction system. The lightest color of the Maillard reaction products was observed when ellagic acid was added at the 90th min, which was the point of time when the Amadori rearrangement product (ARP) developed the most. LC-ESI-MS/MS analysis results showed a significant tendency of the ellagic acid hydrolysis product to react with the predominant intermediate ARP to yield an adduct. The adduct stabilized the ARP and delayed its decomposition and inhibited the downstream reactions toward browning. After the ARP was depleted, ellagic acid also showed an effect on scavenging some short-chain dicarbonyls which contributed to the inhibition of Maillard browning.

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“…The same core region extends in the opposite direction into the other subunit to form a second identical catalytic domain, altogether forming a diagonal channel spanning the protein's diameter where ligands are accommodated. 25,26 The Sj26GST L-site exists in the dimer interface pocket of the channel, 22,27 placing it in proximity to the two catalytic domains, each consisting of the G-and H-sites where glutathione and a reactive electrophile bind respectively 22,28 (Figure 1). It was proposed that the positioning of praziquantel in this site would isolate one of the substrate pairs from each other and disrupt the phase II glutathione conjugation reaction.…”

Section: Introductionmentioning

confidence: 99%

“…Nonetheless, discovery of a nonsubstrate site in the dimer interface established both the Sj26GST and the 28-kDa GST isoform from S. haematobium (Sh28GST) as drug targets for schistosomiasis treatment. 25,27,31,32 Several compounds have since demonstrated schistosome GST binding, causing varying degrees of enzyme inhibition. Among them are the liver test dye reagent bromosulfophthalein (BSP), 32,33 indanyloxyacetic acid, 32 artemether, 34 the polyphenol ellagic acid, 25 as well as anthraquinone dyes.…”

Section: Introductionmentioning

confidence: 99%

Comparative structural analysis of the human and Schistosoma glutathione transferase dimer interface using selective binding of bromosulfophthalein

Valli

Achilonu

2022

Proteins

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The binding channel of Schistosoma glutathione transferase (SGST) has been identified to possess a non-substrate site implicated in enzyme inhibition. This binding channel is formed by the interface of the GST dimer. We produced a comparative characterization of the SGST dimer interface with respect to that of human GST (hGST) analogues using the selective binding of bromosulfophthalein (BSP). First, two SGST and three hGST structures were used as search queries to assemble a data set of 48 empirical GST structures. Sequence alignment to generate a universal residue indexing scheme was then performed, followed by local superposition of the dimer interface. Principal component analysis revealed appreciable variation of the dimer interface, suggesting the potential

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

Cited by 13 publications

References 44 publications

Engineering a Pseudo-26-kDa Schistosoma Glutathione Transferase from bovis/haematobium for Structure, Kinetics, and Ligandin Studies

Engineering a Pseudo-26-kDa Schistosoma Glutathione Transferase from bovis/haematobium for Structure, Kinetics, and Ligandin Studies

Maillard Browning Inhibition by Ellagic Acid via Its Adduct Formation with the Amadori Rearrangement Product

Comparative structural analysis of the human and Schistosoma glutathione transferase dimer interface using selective binding of bromosulfophthalein

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