Effect of geranylated dihydrochalcone from Artocarpus altilis leaves extract on Plasmodium falciparum ultrastructural changes and mitochondrial malate: Quinone oxidoreductase

Hidayati, Agriana Rosmalina; Melinda, Melinda; Ilmi, Hilkatul; Sakura, Takaya; Sakaguchi, Minoru; Ohmori, Junko; Hartuti, Endah Dwi; Tumewu, Lidya; Inaoka, D.K.; Tanjung, Mulyadi; Yoshida, Eri; Tokumasu, Fuyuki; Kita, Kiyoshi; Mori, Masayuki; Dobashi, Kazuyuki; Nozaki, Tomoyoshi; Syafruddin, Din; Hafid, Achmad Fuad; Waluyo, Danang; Widyawaruyanti, Aty

doi:10.1016/j.ijpddr.2022.12.001

Cited by 5 publications

(3 citation statements)

References 44 publications

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“…In general, there are a variety of potent inhibitors, all of which bind to the quinone reaction site in a variety of oxidoreductases that use quinones as substrates. − This implies that the quinone-binding site is a possible druggable site in MQO. Using several approaches including drug screening, compounds have been identified that might inhibit MQO. ,,, However, to the best of our knowledge, no inhibitor has been yet reported that interacts with the quinone-binding site. To explore novel inhibitors targeting MQO, it will be necessary to fully understand the mechanism of action of MQO, for example, by solving the structure of enzyme–substrate complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Using several approaches including drug screening, compounds have been identified that might inhibit MQO. 12 , 14 , 49 , 50 However, to the best of our knowledge, no inhibitor has been yet reported that interacts with the quinone-binding site. To explore novel inhibitors targeting MQO, it will be necessary to fully understand the mechanism of action of MQO, for example, by solving the structure of enzyme–substrate complexes.…”

Section: Discussionmentioning

confidence: 99%

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Insights into the Mechanism of Catalytic Activity of Plasmodium Parasite Malate-Quinone Oxidoreductase

Ito,

Tojo,

Fujii

et al. 2024

ACS Omega

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Plasmodium malate-quinone oxidoreductase (MQO) is a membrane flavoprotein catalyzing the oxidation of malate to oxaloacetate and the reduction of quinone to quinol. Recently, using a yeast expression system, we demonstrated that MQO, expressed in place of mitochondrial malate dehydrogenase (MDH), contributes to the TCA cycle and the electron transport chain in mitochondria, making MQO attractive as a promising drug target in Plasmodium malaria parasites, which lack mitochondrial MDH. However, there is little information on the structure of MQO and its catalytic mechanism, information that will be required to develop novel drugs. Here, we investigated the catalytic site of P. falciparum MQO (PfMQO) using our yeast expression system. We generated a model structure for PfMQO with the AI tool AlphaFold and used protein footprinting by acetylation with acetic anhydride to analyze the surface topology of the model, confirming the computational prediction to be reasonably accurate. Moreover, a putative catalytic site, which includes a possible flavin-binding site, was identified by this combination of protein footprinting and structural prediction model. This active site was analyzed by site-directed mutagenesis. By measuring enzyme activity and protein expression levels in the PfMQO mutants, we showed that several residues at the active site are essential for enzyme function. In addition, a single substitution mutation near the catalytic site resulted in enhanced sensitivity to ferulenol, an inhibitor of PfMQO that competes with malate for binding to the enzyme. This strongly supports the notion that the substrate binds to the proposed catalytic site. Then, the location of the catalytic site was demonstrated by structural comparison with a homologous enzyme. Finally, we used our results to propose a mechanism for the catalytic activity of MQO by reference to the mechanism of action of structurally or functionally homologous enzymes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Insights into the Mechanism of Catalytic Activity of Plasmodium Parasite Malate-Quinone Oxidoreductase

Ito,

Tojo,

Fujii

et al. 2024

ACS Omega

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“…AAL.E.2 isolated 1-(2,4-dihydroxy phenyl)-3-[8-hydroxy-2methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-5yl]-1-propanone, and AAL.E.4 isolated geranyl-2′, 4 ′, 3, 4-tetrahydroxy-dihydrochalcone. Both inhibit P. falciparum and PfMQO enzymes (Hidayati et al, 2023). Further studies are needed on fraction 5 (AAL.E.5) to determine the active substance that acts as an antimalarial agent.…”

Section: Introductionmentioning

confidence: 99%

Antimalarial Potential of Fraction 5 from Ethanolic Leaves Extract of Artocarpus Altilis

Einstenia Kemalahayati,

Hilkatul Ilmi,

Agriana Rosmalina Hidayati

et al. 2023

JFIKI

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Background: Artocarpus altilis leaf extract (AAL.E) was separated by VLC, and six fractions were obtained. Fraction 5 (AAL.E.5) showed antimalarial activity with an IC50 value of 3.71 µg/mL. Objective: This study aimed to determine the antimalarial activity of AAL.E.5 subfractions against P. falciparum, the mechanism of action against Plasmodium Falciparum Malate quinone oxidoreductase (PfMQO), and the active substances. Methods: The AAL.E.5 was separated by open-column chromatography and eluted with chloroform-methanol gradient elution in order of increasing polarity. The antimalarial activity of all subfractions was assessed using a lactate dehydrogenase (LDH) assay against P. falciparum and the mechanism of action of the PfMQO enzyme. The profiles of the most active subfractions were analyzed using High-Performance Liquid Chromatography (HPLC). Results: The separation of fraction 5 (AAL.E.5) yielded 11 subfractions (AAL.E.5.1–AAL.E.5.11). Screening antimalarial activity at 10 μg/mL in this subfraction showed that only five subfractions (AAL.E.5.6-AAL. E.5.10) inhibited P. falciparum and two subfractions (AAL.E.5.6 and AAL.E.5.10) inhibited the PfMQO enzyme. Only subfraction 6 (AAL.E.5.6) inhibited both, with IC50 values of 6.609 µg/mL and 20.34 µg/mL. The thin layer chromatography profile of AAL.E.5.6 revealed reddish-orange spots, indicating the presence of flavonoid compounds, and was also presumed from the UV-visible to HPLC chromatogram for band I in the 300 – 400 nm range and band II in the 240–285 nm range. Conclusion: Subfraction 6 has antimalarial activity against P. falciparum and is thought to have a mechanism of action in PfMQO. Based on the TLC, HPLC, and UV-Vis spectra, subfraction 6 was assumed to be a flavonoid.

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Exploring potential Plasmodium kinase inhibitors: a combined docking, MD and QSAR studies

Kankinou,

Yildiz,

Kocak

2023

Journal of Biomolecular Structure and Dynamics

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Effect of geranylated dihydrochalcone from Artocarpus altilis leaves extract on Plasmodium falciparum ultrastructural changes and mitochondrial malate: Quinone oxidoreductase

Cited by 5 publications

References 44 publications

Insights into the Mechanism of Catalytic Activity of Plasmodium Parasite Malate-Quinone Oxidoreductase

Insights into the Mechanism of Catalytic Activity of Plasmodium Parasite Malate-Quinone Oxidoreductase

Antimalarial Potential of Fraction 5 from Ethanolic Leaves Extract of Artocarpus Altilis

Exploring potential Plasmodium kinase inhibitors: a combined docking, MD and QSAR studies

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