Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor

Valenciano, Ana Lisa; Fernández-Murga, M. Leonor; Merino, Emilio F.; Holderman, Nicole R.; Butschek, Grant J.; Shaffer, Karl J.; Tyler, Peter C.; Cassera, María B.

doi:10.1038/s41598-019-50319-5

Cited by 9 publications

(17 citation statements)

References 64 publications

(87 reference statements)

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“…Thus, we hypothesized that a similar scenario may occur between actively diving asexual stages and nondividing gametocyte stages of P. falciparum. To assess this hypothesis, we performed metabolomics analysis by LC-HRMS as we described previously 41 . In the asexual schizont stage, we detected the presence of both polyprenols and dolichols of 15 to 19 isoprene units with isoprenologues 15, 16 and 17 being the predominant species ( Fig.…”

Section: Medium-long Polyprenols and Dolichols Are Present In The Asementioning

confidence: 99%

“…Extraction of metabolites and LC-HRMS analysis was performed as we previously described 41 . Briefly, 1 mL cold methanol was added to each sample and three consecutive extractions with 2 mL of hexane followed by pulse-vortex for 1 min and 10 min sonication in an ultrasonic bath.…”

Section: Sample Preparation and Polyisoprenoid Profiling By Lc-hrmsmentioning

confidence: 99%

“…Analysis of polyisoprenoids was performed on an ionKey/MS system composed of an ACQUITY UPLC M-Class, the ionKey source, and an iKey HSS T3, 100 Å, 1.8 µm (particle size), 150 µm × 100 mm column coupled to a SYNAPT G2-Si mass spectrometer (Waters Corporation, Milford, MA, USA). Isoprenoid separation was accomplished as described previously 41 and a representative extracted ion chromatogram is shown in Supplementary Fig. S4.…”

Section: Sample Preparation and Polyisoprenoid Profiling By Lc-hrmsmentioning

confidence: 99%

“…C]glucose, cultures in ring stage (5% hematocrit and 7% parasitemia) were first incubated in glucose-free RPMI 1640 for 2 h and then supplemented with 4 g/L of [1-13 C]glucose for 22-24 h. RPMI 1640 without glucose was prepared as we described previously41 . For metabolic labeling experiments using[3][4][5][6][7][8][9][10][11][12][13] C]IPP, cultures in ring stage were first treated with 10 µM fosmidomycin for 2 h and then supplemented with [3-13 C]IPP:IPP (1:1, 200 µM) in the presence of fosmidomycin.…”

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confidence: 99%

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Metabolomics profiling reveals new aspects of dolichol biosynthesis inPlasmodium falciparum

Zimbres¹,

Valenciano²,

Merino³

et al. 2019

Preprint

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The cis-polyisoprenoid lipids namely polyprenols, dolichols and their derivatives are linear polymers of several isoprene units. In eukaryotes, polyprenols and dolichols are synthesized as a mixture of four or more homologues of different length with one or two predominant species with sizes varying among organisms. Polyprenols have been hardly detectable in eukaryotic cells under normal conditions with the exception of plants and sporulating yeast. Our metabolomics studies revealed that cis-polyisoprenoids are more prevalent and diverse in the parasite Plasmodium falciparum than previously postulated as we uncovered active de novo biosynthesis and substantial levels of accumulation of polyprenols and dolichols of 15 to 19 isoprene units. A distinctive polyprenol and dolichol profile both within the intraerythrocytic asexual cycle and between asexual and gametocyte stages was also observed suggesting that cis-polyisoprenoid biosynthesis changes throughout parasite's development. In addition, we confirmed the presence of an active cisprenyltransferase (PfCPT) and that dolichol biosynthesis occurs via reduction of the polyprenol to dolichol by an active polyprenol reductase (PfPPRD) in the malaria parasite. Isotopic labeling and metabolomic analyses of a conditional mutant of PfCPT or PfPPRD suggest that polyprenols may be able to substitute dolichols in their biological functions when dolichol synthesis is impaired in Plasmodium.Malaria is caused by protozoan parasites of the genus Plasmodium and most cases of lifethreatening malaria are attributable to infection with Plasmodium falciparum. The parasite has a complex life cycle that involves the human host and its vector, the Anopheles mosquitoes. All clinical features are caused during the asexual intraerythrocytic life cycle due to the repeated invasion of human red blood cells (RBCs). The asexual intraerythrocytic developmental cycle of P. falciparum lasts around 48 h, during which the parasite progresses through four morphologically different stages: ring, trophozoite, and schizont stages, ending with rupture of the erythrocyte and release of merozoites that will invade new erythrocytes. Transmission of the malaria parasite requires development of male and female gametocytes (gametocytogenesis), which are ingested by female mosquitoes during a blood meal and undergo sexual reproduction in the mosquito's midgut. Nondividing P. falciparum gametocytes take between 10 and 12 2 days to fully mature and progress through five morphologically distinct forms (stages I to V), which are different from other Plasmodium species.During their complex life cycle malaria parasites encounter different nutritional environments within and between hosts. The presence of de novo and salvage pathways gives parasites a great metabolic flexibility to cope with those changes 1,2 . For example, mature RBCs are capable of only a few metabolic functions since transcription and translation is not present in these cells. However, a wide variety of metabolites are available to the parasite i...

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Section: Medium-long Polyprenols and Dolichols Are Present In The Asementioning

confidence: 99%

Section: Sample Preparation and Polyisoprenoid Profiling By Lc-hrmsmentioning

confidence: 99%

Section: Sample Preparation and Polyisoprenoid Profiling By Lc-hrmsmentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolomics profiling reveals new aspects of dolichol biosynthesis inPlasmodium falciparum

Zimbres¹,

Valenciano²,

Merino³

et al. 2019

Preprint

Self Cite

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show abstract

“…Thus, we hypothesized that a similar scenario may occur between actively diving asexual stages and nondividing gametocyte stages of P. falciparum. To assess this hypothesis, we performed metabolomics analysis by LC-HRMS as we described previously 40 . In the asexual schizont stage, we detected the presence of both polyprenols and dolichols of 15 to 19 isoprene units with isoprenologues 15, 16 and 17 being the predominant species ( Fig.…”

mentioning

confidence: 99%

Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

Zimbres

Valenciano

Merino

et al. 2020

Sci Rep

Self Cite

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the cis-polyisoprenoid lipids namely polyprenols, dolichols and their derivatives are linear polymers of several isoprene units. In eukaryotes, polyprenols and dolichols are synthesized as a mixture of four or more homologues of different length with one or two predominant species with sizes varying among organisms. Interestingly, co-occurrence of polyprenols and dolichols, i.e. detection of a dolichol along with significant levels of its precursor polyprenol, are unusual in eukaryotic cells. Our metabolomics studies revealed that cis-polyisoprenoids are more diverse in the malaria parasite Plasmodium falciparum than previously postulated as we uncovered active de novo biosynthesis and substantial levels of accumulation of polyprenols and dolichols of 15 to 19 isoprene units. A distinctive polyprenol and dolichol profile both within the intraerythrocytic asexual cycle and between asexual and gametocyte stages was observed suggesting that cis-polyisoprenoid biosynthesis changes throughout parasite's development. Moreover, we confirmed the presence of an active cis-prenyltransferase (PfCPT) and that dolichol biosynthesis occurs via reduction of the polyprenol to dolichol by an active polyprenol reductase (PfPPRD) in the malaria parasite. Malaria is caused by protozoan parasites of the genus Plasmodium and most cases of life-threatening malaria are attributable to infection with Plasmodium falciparum. The parasite has a complex life cycle that involves the human host and its vector, the Anopheles mosquitoes. All clinical features are caused during the asexual intraerythrocytic life cycle due to the repeated invasion of human red blood cells (RBCs). The asexual intraerythrocytic developmental cycle of P. falciparum lasts around 48 h, during which the parasite progresses through four morphologically different stages: ring, trophozoite, and schizont stages, ending with rupture of the erythrocyte and release of merozoites that will invade new erythrocytes. Transmission of the malaria parasite requires development of male and female gametocytes (gametocytogenesis), which are ingested by female mosquitoes during a blood meal and undergo sexual reproduction in the mosquito's midgut. Nondividing P. falciparum gametocytes take between 10 and 12 days to fully mature and progress through five morphologically distinct forms (stages I to V), which are different from other Plasmodium species. During their complex life cycle malaria parasites encounter different nutritional environments within and between hosts. The presence of de novo and salvage pathways gives parasites a great metabolic flexibility to cope with those changes 1,2. For example, mature RBCs are capable of only a few metabolic functions since transcription and translation is not present in these cells. However, a wide variety of metabolites are available to the parasite in the human plasma 3. Among the metabolic pathways that become inactive in mature RBCs is the mevalonate pathway which synthesizes the isoprenoid building blocks isopentenyl diphosphate (IPP) and d...

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Recent metabolomic developments for antimalarial drug discovery

et al. 2022

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Malaria is a parasitic disease that remains a global health issue, responsible for a significant death and morbidity toll. Various factors have impacted the use and delayed the development of antimalarial therapies, such as the associated financial cost and parasitic resistance. In order to discover new drugs and validate parasitic targets, a powerful omics tool, metabolomics, emerged as a reliable approach. However, as a fairly recent method in malaria, new findings are timely and original practices emerge frequently. This review aims to discuss recent research towards the development of new metabolomic methods in the context of uncovering antiplasmodial mechanisms of action in vitro and to point out innovative metabolic pathways that can revitalize the antimalarial pipeline.

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Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor

Cited by 9 publications

References 64 publications

Metabolomics profiling reveals new aspects of dolichol biosynthesis inPlasmodium falciparum

Metabolomics profiling reveals new aspects of dolichol biosynthesis inPlasmodium falciparum

Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

Recent metabolomic developments for antimalarial drug discovery

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