Nornidulin, A New Inhibitor of Plasmodium falciparum Malate: Quinone Oxidoreductase (PfMQO) from Indonesian Aspergillus sp. BioMCC f.T.8501

Cahyono, Alfian Wika; Fitri, Loeki Enggar; Winarsih, Sri; Prabandari, Erwahyuni Endang; Waluyo, Danang; Pramisandi, Amila; Chrisnayanti, Evita; Dewi, Diana; Siska, Eka; Nurlaila, Nurlaila; Nugroho, Nuki Bambang; Nozaki, Tomoyoshi; Suciati, Suciati

doi:10.3390/ph16020268

Cited by 7 publications

(5 citation statements)

References 22 publications

(27 reference statements)

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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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“…Saponins, on the other hand, possess antimalarial properties by causing erythrocytes to lyse through the destruction of their cell membranes [35,36]. Alkaloids have demonstrated the ability to decrease parasitemia levels by inhibiting the synthesis of parasite DNA and RNA [37]. While steroids and their derivatives have also been found to have antimalarial effects in various studies, the specific mechanism remains unclear.…”

Section: C1 (Negative Control) C2 (Positive Control Receiving Artemis...mentioning

confidence: 99%

Untitled

2024

J. Med. Chem. Sci.

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Background: Malaria poses a substantial threat to healthcare systems across the globe. The escalating resistance of malaria parasites to the absence of affordable and accessible antimalarial medications has exacerbated the challenges associated with malaria treatment. This research aims to evaluate the antimalarial and antioxidant properties of Stichopus hermanni in combination with artemisinin, employing murine malaria models. Method: This study employed the 4-day suppression test procedure and conducted an experimental investigation with a post-test-only control group design. The study involved 35 male BALB/c mice, aged 7-10 weeks, each infected with Plasmodium berghei ANKA/PbA. The sample was divided into five groups: C1 (negative control), C2 (positive control), T1 (administered 15 mg/Kg BW/day of Stichopus hermanni ethanol extract and 0.04 mg/g BW/day of artemisinin), T2 (administered 17 mg/Kg BW/day of Stichopus hermanni ethanol extract and 0.04 mg/g BW/day of artemisinin), and T3 (administered 20 mg/Kg BW/day of Stichopus hermanni ethanol extract and 0.04 mg/g BW/day of artemisinin). The parameters measured included % parasitemia level, % growth inhibition, and malondialdehyde (MDA) levels. Results: The T3 group exhibited the lowest parasitemia level and the highest degree of growth inhibition compared to the other groups (p-value < 0.05). However, statistically, it did not differ significantly from C2 and T1. Meanwhile, the T3 group demonstrated the lowest MDA levels and the most significant antioxidant capacity compared to the other groups (pvalue < 0.05). Conclusion: Based on both descriptive and statistical analyses, the combination of Stichopus hermanni ethanol extract and artemisinin exhibits antimalarial and antioxidant activities.

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“…Malaria eradication has resulted in a decrease in morbidity and mortality [1]. Still, malaria control efforts over the last decade have been ineffective [2]. Malaria control is made worse by the COVID-19 pandemic, which affects the decline and slowdown of care for this infectious disease.…”

Section: Introductionmentioning

confidence: 99%

“…Malaria control is made worse by the COVID-19 pandemic, which affects the decline and slowdown of care for this infectious disease. This condition increased morbidity rates of 240 million cases and a mortality rate of around 627 thousand [2,3]. During the last 20 years, artemisinin combination treatment, or ACT, has been the main medication for treating various malaria infections.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2023

J. Med. Chem. Sci.

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Background: Malaria resistance to artemisinin combination therapy has prompted researchers to explore anti-plasmodium materials. One of the marine biotas thought to have the potential to inhibit the development of malaria parasites (Plasmodium sp) are black trepang and curryfish. These two marine biotas consist of two varieties of sea cucumbers with various therapeutic benefits. However, their antimalarial effects have not been studied. Objective: Two marine biotas, black trepang and curryfish extract, were analyzed using in vitro screening to determine their antimalarial activity. Methods: The experiment was done through in vitro screening technique (culture medium containing P. falciparum). P1 was a negative control; P2 was a positive control/using chloroquine as an antimalarial; P3 was a group that received black trepang extract) and P4 was a group that received curryfish extract. Measurements of parasitemia levels, growth percentage, inhibition rate, and IC50 were performed to determine the antimalarial activity. Results: The antimalarial results suggest that increasing the dose of marine biota extract reduces the parasite development rate and increases the inhibition rate. In line with IC50 analysis, both marine biotas have high antimalarial activity. Curryfish extract has a lower IC50 value than black trepang extract. Conclusion:The study demonstrated that black trepang and curry fish have high antimalarial activity.

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Nornidulin, A New Inhibitor of Plasmodium falciparum Malate: Quinone Oxidoreductase (PfMQO) from Indonesian Aspergillus sp. BioMCC f.T.8501

Cited by 7 publications

References 22 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

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