Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

Flavia M. Zimbres; Ana Lisa Valenciano; Emilio F. Merino; Anat Florentin; Nicole R. Holderman; Guijuan He; Katarzyna Gawarecka; Karolina Skorupinska-Tudek; Maria L. Fernández-Murga; Ewa Swiezewska; Xiaofeng Wang; Vasant Muralidharan; Maria Belen Cassera

doi:10.1038/s41598-020-70246-0

Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

Flavia M. Zimbres, Ana Lisa Valenciano, Emilio F. Merino, Anat Florentin, Nicole R. Holderman, Guijuan He, Katarzyna Gawarecka, Karolina Skorupinska-Tudek, Maria L. Fernández-Murga, Ewa Swiezewska, Xiaofeng Wang, Vasant Muralidharan, Maria Belen Cassera^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	American English
Article number	13264
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-70246-0
State	Published - 1 Dec 2020
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (AI108819 to M.B.C.) and American Heart Association Postdoctoral Fellowship (18POST34080315 to A.F.). The following reagents were obtained through MR4 as part of the BEI Resources Repository, NIAID, NIH: P. falciparum, strain NF54 (MRA-1000), contributed by M. Dowler, Walter Reed Army Institute of research and strain 3D7 (MRA-102) contributed by Daniel J. Carucci. We thank Julie Nelson for providing access to CTEGD flow cytometry core facility and Muthugapatti Kandasamy at the Biomedical Microscopy Core at the University of Georgia for help with microscopy. We thank Dennis Kyle for the gift of [3-13C]IPP. The yeast strains were kindly supplied to E.S. by Vincent Cantagrel. We thank Grant Butschek for comments and corrections.

Publisher Copyright:
© 2020, The Author(s).

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Zimbres, F. M., Valenciano, A. L., Merino, E. F., Florentin, A., Holderman, N. R., He, G., Gawarecka, K., Skorupinska-Tudek, K., Fernández-Murga, M. L., Swiezewska, E., Wang, X., Muralidharan, V., & Cassera, M. B. (2020). Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum. Scientific Reports, 10(1), Article 13264. https://doi.org/10.1038/s41598-020-70246-0

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title = "Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum",

abstract = "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{\textquoteright}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.",

author = "Zimbres, {Flavia M.} and Valenciano, {Ana Lisa} and Merino, {Emilio F.} and Anat Florentin and Holderman, {Nicole R.} and Guijuan He and Katarzyna Gawarecka and Karolina Skorupinska-Tudek and Fern{\'a}ndez-Murga, {Maria L.} and Ewa Swiezewska and Xiaofeng Wang and Vasant Muralidharan and Cassera, {Maria Belen}",

note = "Funding Information: This work was supported by the National Institutes of Health (AI108819 to M.B.C.) and American Heart Association Postdoctoral Fellowship (18POST34080315 to A.F.). The following reagents were obtained through MR4 as part of the BEI Resources Repository, NIAID, NIH: P. falciparum, strain NF54 (MRA-1000), contributed by M. Dowler, Walter Reed Army Institute of research and strain 3D7 (MRA-102) contributed by Daniel J. Carucci. We thank Julie Nelson for providing access to CTEGD flow cytometry core facility and Muthugapatti Kandasamy at the Biomedical Microscopy Core at the University of Georgia for help with microscopy. We thank Dennis Kyle for the gift of [3-13C]IPP. The yeast strains were kindly supplied to E.S. by Vincent Cantagrel. We thank Grant Butschek for comments and corrections. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41598-020-70246-0",

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Zimbres, FM, Valenciano, AL, Merino, EF, Florentin, A, Holderman, NR, He, G, Gawarecka, K, Skorupinska-Tudek, K, Fernández-Murga, ML, Swiezewska, E, Wang, X, Muralidharan, V & Cassera, MB 2020, 'Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum', Scientific Reports, vol. 10, no. 1, 13264. https://doi.org/10.1038/s41598-020-70246-0

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T1 - Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

AU - Zimbres, Flavia M.

AU - Valenciano, Ana Lisa

AU - Merino, Emilio F.

AU - Florentin, Anat

AU - Holderman, Nicole R.

AU - He, Guijuan

AU - Gawarecka, Katarzyna

AU - Skorupinska-Tudek, Karolina

AU - Fernández-Murga, Maria L.

AU - Swiezewska, Ewa

AU - Wang, Xiaofeng

AU - Muralidharan, Vasant

AU - Cassera, Maria Belen

N1 - Funding Information: This work was supported by the National Institutes of Health (AI108819 to M.B.C.) and American Heart Association Postdoctoral Fellowship (18POST34080315 to A.F.). The following reagents were obtained through MR4 as part of the BEI Resources Repository, NIAID, NIH: P. falciparum, strain NF54 (MRA-1000), contributed by M. Dowler, Walter Reed Army Institute of research and strain 3D7 (MRA-102) contributed by Daniel J. Carucci. We thank Julie Nelson for providing access to CTEGD flow cytometry core facility and Muthugapatti Kandasamy at the Biomedical Microscopy Core at the University of Georgia for help with microscopy. We thank Dennis Kyle for the gift of [3-13C]IPP. The yeast strains were kindly supplied to E.S. by Vincent Cantagrel. We thank Grant Butschek for comments and corrections. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41598-020-70246-0

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JO - Scientific Reports

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Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

Abstract

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