Redox‐dependent lipoylation of mitochondrial proteins in <scp><i>P</i></scp><i>lasmodium falciparum</i>

Afanador, Gustavo A.; Matthews, Krista Ann; Bartee, David; Gisselberg, Jolyn E.; Walters, Maroya Spalding; Meyers, Caren L. Freel; Prigge, Sean T.

doi:10.1111/mmi.12753

Cited by 19 publications

(62 citation statements)

References 57 publications

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“…LplA2 is partially redundant with LipB, and represents an alternate first step in the apicoplast lipoic acid synthesis pathway [84]. However, as LplA2 is also targeted to the mitochondrion [84] and required for the lipoylation of two enzyme complexes there [161], the enzyme appears to have multiple roles in lipoic acid metabolism.…”

Section: The Lipoic Acid Synthesis Pathwaymentioning

confidence: 92%

“…The activity of PfLplA2 has been investigated using several approaches, and its function as a lipoate protein ligase is supported its ability to lipoylate the bacterial PDH when recombinantly expressed [83,161]. However, conflicting results for complementation and in vitro activity assays [83,84,161] suggest PfLplA2 is at best a poor lipoate protein ligase, and indicate its primary function is instead as an accessory to LplA1 in the mitochondrion [161].…”

Section: Lipoate Protein Ligase (Lpla2)mentioning

confidence: 98%

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Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Shears

Botté

McFadden

2015

Molecular and Biochemical Parasitology

104

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The malaria parasite Plasmodium possesses a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is essential for parasite survival, and harbors several plant-like metabolic pathways including a type II fatty acid synthesis (FASII) pathway. The FASII pathway was discovered in 1998, and much of the early research in the field pursued it as a therapeutic drug target. These studies identified a range of compounds with activity against bloodstage parasites and led to the localization and characterization of most enzymes in the pathway. However, when genetic studies revealed FASII was dispensable in bloodstage parasites, it effectively discounted the pathway as a therapeutic drug target, and suggested these compounds instead interfered with other processes. Interest in FASII then shifted toward its disruption for malaria prophylaxis and vaccine development, with experiments in rodent malaria models identifying a crucial role for the pathway in the parasite's transition from the liver to the blood. Unexpectedly however, the human malaria parasite P. falciparum was recently found to differ from rodent models and require FASII for mosquito stage development. This requirement blocked the production of the FASII-deficient forms that might be used as a genetically attenuated parasite vaccine, suggesting the pathway was also unsuitable as a vaccine target. This review discusses how perception of FASII has changed over time, and presents key findings about each enzyme in the pathway to identify remaining questions and opportunities for malaria control.

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Section: The Lipoic Acid Synthesis Pathwaymentioning

confidence: 92%

Section: Lipoate Protein Ligase (Lpla2)mentioning

confidence: 98%

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Shears

Botté

McFadden

2015

Molecular and Biochemical Parasitology

104

View full text Add to dashboard Cite

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“…A, lanes 2–3). This is consistent with the previous observation that Pf LipL1 is unable to lipoylate the BCDH LD or KDH LD in a ligation reaction (Afanador et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…Previous work showed that reduced lipoate is a requirement for the lipoylation of BCDH LD and KDH LD (Afanador et al ., ). Since Pf LipL2 catalyzed the attachment of lipoate, we hypothesized that Pf LipL2 only recognizes the reduced state of lipoyl‐AMP.…”

Section: Resultsmentioning

confidence: 97%

“…BCDH and KDH are lipoylated through a second mechanism that requires both Pf LipL1 and Pf LipL2 (Afanador et al ., ). These two lipoylation pathways have a strong dependence on the lipoate redox state since lipoylation of the BCDH and KDH requires fully reduced lipoate (dihydrolipoate), while lipoylation of the H‐protein does not (Afanador et al ., ). This redox‐dependent mechanism of controlling lipoate metabolism has not been described in other organisms.…”

Section: Introductionmentioning

confidence: 97%

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A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species

Afanador

Guerra

Swift

et al. 2017

Molecular Microbiology

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Summary Lipoate is an essential cofactor for enzymes that are important for central metabolism and other processes. In malaria parasites, scavenged lipoate from the human host is required for survival. The Plasmodium falciparum mitochondrion contains two enzymes (PfLipL1 and PfLipL2) that are responsible for activating mitochondrial proteins through the covalent attachment of lipoate (lipoylation). Lipoylation occurs via a novel redox-gated mechanism that remains poorly understood. We show that PfLipL1 functions as a redox switch that determines which downstream proteins will be activated. Based on the lipoate redox state, PfLipL1 either functions as a canonical lipoate ligase or as a lipoate activating enzyme which works in conjunction with PfLipL2. We demonstrate that PfLipL2 is a lipoyltransferase and is a member of a novel clade of lipoate attachment enzymes. We show that a LipL2 enzyme from Chlamydia trachomatis has similar activity, demonstrating conservation between intracellular pathogens from different phylogenetic kingdoms and supporting the hypothesis that an early ancestor of malaria parasites once contained a chlamydial endosymbiont. Redox-dependent lipoylation may regulate processes such as central metabolism and oxidative defense pathways.

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Eine chemisch‐proteomische Strategie identifiziert Inhibitoren der Lipoat‐Wiederverwertung in Bakterien und Parasiten

et al. 2023

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Die Entwicklung neuer Antiinfektiva erfordert innovative Strategien zur gezielten Ausnutzung von Stoffwechselwegen in Krankheitserregern, die in menschlichen Zellen abwesend sind. Basierend auf diesem Prinzip haben wir Hemmstoffe der Liponsäure (LA) Wiederverwertung entwickelt, einem entscheidenden Stoffwechselweg für das Überleben von LA‐auxotrophen Bakterien und Parasiten, der jedoch in menschlichen Zellen nicht essentiell ist. Eine auf LA basierende Sonde wurde selektiv über die Lipoatproteinligase (LPL) auf Substratproteine in intakten Zellen übertragen, und ihre Bindungsstellen wurden mittels Massenspektrometrie bestimmt. Die Intensität der Markierung mit der Sonde diente als Maß für die Aktivität von LPL und ermöglichte intrazelluläre Selektion für zellpermeable LPL‐Hemmer. Das Testen einer vorselektierten Substanzbibliothek ergab zwei Substratanaloga (LAMe und C3) als Hemmstoffe, die durch Bindungsstudien und Co‐Kristallographie weiter validiert wurden. Bemerkenswert ist, dass LAMe eine geringe Toxizität in menschlichen Zellen aufwies und eine Abtötung von Plasmodium falciparum in Erythrozyten mit einem EC50‐Wert von 15 μM erreichte, was diesen Stoff zum bisher wirksamsten LPL‐Hemmer macht, der jeher berichtet wurde.

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Redox‐dependent lipoylation of mitochondrial proteins in Plasmodium falciparum

Cited by 19 publications

References 57 publications

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species

Eine chemisch‐proteomische Strategie identifiziert Inhibitoren der Lipoat‐Wiederverwertung in Bakterien und Parasiten

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