The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites

Euna Yoo; Christopher J. Schulze; Barbara H. Stokes; Ouma Onguka; Tomas Yeo; Sachel Mok; Nina F. Gnädig; Yani Zhou; Kenji Kurita; Ian T. Foe; Stephanie M. Terrell; Michael J. Boucher; Piotr Cieplak; Krittikorn Kumpornsin; Marcus C.S. Lee; Roger G. Linington; Jonathan Z. Long; Anne Catrin Uhlemann; Eranthie Weerapana; David A. Fidock; Matthew Bogyo

doi:10.1016/j.chembiol.2020.01.001

The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites

Euna Yoo
, Christopher J. Schulze
, Barbara H. Stokes
, Ouma Onguka
, Tomas Yeo
, Sachel Mok
, Nina F. Gnädig
, Yani Zhou
, Kenji Kurita
, Ian T. Foe
, Stephanie M. Terrell
, Michael J. Boucher
, Piotr Cieplak
, Krittikorn Kumpornsin
, Marcus C.S. Lee
, Roger G. Linington
, Jonathan Z. Long
, Anne Catrin Uhlemann
, Eranthie Weerapana
, David A. Fidock

Matthew Bogyo (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

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

53 Citations (Scopus)

Abstract

Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets. Using a probe analog of the antimalarial natural product Sal A, Yoo et al. identify its targets as multiple essential serine hydrolases, including a homolog of human monoacylglycerol lipase. Because parasites were unable to generate robust in vitro resistance to Sal A, these enzymes represent promising targets for antimalarial drugs.

Original language	English
Pages (from-to)	143-157
Number of pages	15
Journal	Cell Chemical Biology
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2020.01.001
Publication status	Published - 23 Jan 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

activity-based probes
chemical proteomics
lipid metabolism
malaria
natural products
Plasmodium falciparum
Salinipostin A
serine hydrolases

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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Cite this

Yoo, E., Schulze, C. J., Stokes, B. H., Onguka, O., Yeo, T., Mok, S., Gnädig, N. F., Zhou, Y., Kurita, K., Foe, I. T., Terrell, S. M., Boucher, M. J., Cieplak, P., Kumpornsin, K., Lee, M. C. S., Linington, R. G., Long, J. Z., Uhlemann, A. C., Weerapana, E., ... Bogyo, M. (2020). The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites. Cell Chemical Biology, 27(2), 143-157. https://doi.org/10.1016/j.chembiol.2020.01.001

@article{b4bccaeb9bca48cca6eddedcc59ff89e,

title = "The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites",

abstract = "Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets. Using a probe analog of the antimalarial natural product Sal A, Yoo et al. identify its targets as multiple essential serine hydrolases, including a homolog of human monoacylglycerol lipase. Because parasites were unable to generate robust in vitro resistance to Sal A, these enzymes represent promising targets for antimalarial drugs.",

keywords = "activity-based probes, chemical proteomics, lipid metabolism, malaria, natural products, Plasmodium falciparum, Salinipostin A, serine hydrolases",

author = "Euna Yoo and Schulze, \{Christopher J.\} and Stokes, \{Barbara H.\} and Ouma Onguka and Tomas Yeo and Sachel Mok and Gn{\"a}dig, \{Nina F.\} and Yani Zhou and Kenji Kurita and Foe, \{Ian T.\} and Terrell, \{Stephanie M.\} and Boucher, \{Michael J.\} and Piotr Cieplak and Krittikorn Kumpornsin and Lee, \{Marcus C.S.\} and Linington, \{Roger G.\} and Long, \{Jonathan Z.\} and Uhlemann, \{Anne Catrin\} and Eranthie Weerapana and Fidock, \{David A.\} and Matthew Bogyo",

note = "Funding Information: We thank Daniel Goldberg for sharing the parasites expressing WT and active site mutant (S179T) PfPARE-GFP fusions. We thank Benjamin Cravatt for providing human MAGL inhibitors and a library of triazole urea-containing compounds. We also thank Ellen Yeh for access to the BD Accuri flow cytometer and helpful discussion. We thank Edgar Deu for his efforts to generate a conditional knockout of PfMAGLLP. We thank Micah Niphakis and Kenneth Lum for the sequence and phylogenetic analysis of serine hydrolases and advice. Funding for this work was provided by NIH NIAID R33 AI127581 (to M.B. and D.A.F.), NIH NIGMS R01GM117004 and R01GM118431 (to E.W.), NIH NIDDK DK105203 and P30DK116074 (to J.Z.L.), and NSERC Discovery (to R.G.L.). Funding Information: We thank Daniel Goldberg for sharing the parasites expressing WT and active site mutant (S179T) PfPARE-GFP fusions. We thank Benjamin Cravatt for providing human MAGL inhibitors and a library of triazole urea-containing compounds. We also thank Ellen Yeh for access to the BD Accuri flow cytometer and helpful discussion. We thank Edgar Deu for his efforts to generate a conditional knockout of PfMAGLLP. We thank Micah Niphakis and Kenneth Lum for the sequence and phylogenetic analysis of serine hydrolases and advice. Funding for this work was provided by NIH NIAID R33 AI127581 (to M.B. and D.A.F.), NIH NIGMS R01GM117004 and R01GM118431 (to E.W.), NIH NIDDK DK105203 and P30DK116074 (to J.Z.L.), and NSERC Discovery (to R.G.L.). Conceptualization, E.Y. C.J.S. E.W. and M.B.; Methodology, J.Z.L. A.-C.U. E.W. D.A.F. and M.B.; Formal Analysis, E.Y. C.J.S. B.H.S. T.Y. Y.Z. K. Kurita, P.C. J.Z.L. E.W. D.A.F. and M.B.; Investigation, E.Y. C.J.S. B.H.S. O.O. T.Y. S.M. N.F.G. K. Kurita, K. Kumpornsin, I.T.F. S.M.T. M.J.B. P.C. and E.W.; Writing ?? Original Draft, E.Y. C.J.S. and, M.B.; Writing ?? Review \& Editing, E.Y. C.J.S. B.H.S. D.A.F. and M.B.; Resources, R.G.L. J.Z.L. A.-C.U. E.W. D.A.F. and M.B.; Supervision, M.C.S.L. E.W. D.A.F. and M.B.; Funding Acquisition, M.C.S.L. R.G.L. J.Z.L. E.W. D.A.F. and M.B. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Ltd",

year = "2020",

month = jan,

day = "23",

doi = "10.1016/j.chembiol.2020.01.001",

language = "English",

volume = "27",

pages = "143--157",

journal = "Cell Chemical Biology",

issn = "2451-9456",

publisher = "Elsevier",

number = "2",

}

Yoo, E, Schulze, CJ, Stokes, BH, Onguka, O, Yeo, T, Mok, S, Gnädig, NF, Zhou, Y, Kurita, K, Foe, IT, Terrell, SM, Boucher, MJ, Cieplak, P, Kumpornsin, K, Lee, MCS, Linington, RG, Long, JZ, Uhlemann, AC, Weerapana, E, Fidock, DA & Bogyo, M 2020, 'The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites', Cell Chemical Biology, vol. 27, no. 2, pp. 143-157. https://doi.org/10.1016/j.chembiol.2020.01.001

TY - JOUR

T1 - The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites

AU - Yoo, Euna

AU - Schulze, Christopher J.

AU - Stokes, Barbara H.

AU - Onguka, Ouma

AU - Yeo, Tomas

AU - Mok, Sachel

AU - Gnädig, Nina F.

AU - Zhou, Yani

AU - Kurita, Kenji

AU - Foe, Ian T.

AU - Terrell, Stephanie M.

AU - Boucher, Michael J.

AU - Cieplak, Piotr

AU - Kumpornsin, Krittikorn

AU - Lee, Marcus C.S.

AU - Linington, Roger G.

AU - Long, Jonathan Z.

AU - Uhlemann, Anne Catrin

AU - Weerapana, Eranthie

AU - Fidock, David A.

AU - Bogyo, Matthew

N1 - Funding Information: We thank Daniel Goldberg for sharing the parasites expressing WT and active site mutant (S179T) PfPARE-GFP fusions. We thank Benjamin Cravatt for providing human MAGL inhibitors and a library of triazole urea-containing compounds. We also thank Ellen Yeh for access to the BD Accuri flow cytometer and helpful discussion. We thank Edgar Deu for his efforts to generate a conditional knockout of PfMAGLLP. We thank Micah Niphakis and Kenneth Lum for the sequence and phylogenetic analysis of serine hydrolases and advice. Funding for this work was provided by NIH NIAID R33 AI127581 (to M.B. and D.A.F.), NIH NIGMS R01GM117004 and R01GM118431 (to E.W.), NIH NIDDK DK105203 and P30DK116074 (to J.Z.L.), and NSERC Discovery (to R.G.L.). Funding Information: We thank Daniel Goldberg for sharing the parasites expressing WT and active site mutant (S179T) PfPARE-GFP fusions. We thank Benjamin Cravatt for providing human MAGL inhibitors and a library of triazole urea-containing compounds. We also thank Ellen Yeh for access to the BD Accuri flow cytometer and helpful discussion. We thank Edgar Deu for his efforts to generate a conditional knockout of PfMAGLLP. We thank Micah Niphakis and Kenneth Lum for the sequence and phylogenetic analysis of serine hydrolases and advice. Funding for this work was provided by NIH NIAID R33 AI127581 (to M.B. and D.A.F.), NIH NIGMS R01GM117004 and R01GM118431 (to E.W.), NIH NIDDK DK105203 and P30DK116074 (to J.Z.L.), and NSERC Discovery (to R.G.L.). Conceptualization, E.Y. C.J.S. E.W. and M.B.; Methodology, J.Z.L. A.-C.U. E.W. D.A.F. and M.B.; Formal Analysis, E.Y. C.J.S. B.H.S. T.Y. Y.Z. K. Kurita, P.C. J.Z.L. E.W. D.A.F. and M.B.; Investigation, E.Y. C.J.S. B.H.S. O.O. T.Y. S.M. N.F.G. K. Kurita, K. Kumpornsin, I.T.F. S.M.T. M.J.B. P.C. and E.W.; Writing ?? Original Draft, E.Y. C.J.S. and, M.B.; Writing ?? Review & Editing, E.Y. C.J.S. B.H.S. D.A.F. and M.B.; Resources, R.G.L. J.Z.L. A.-C.U. E.W. D.A.F. and M.B.; Supervision, M.C.S.L. E.W. D.A.F. and M.B.; Funding Acquisition, M.C.S.L. R.G.L. J.Z.L. E.W. D.A.F. and M.B. The authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Ltd

PY - 2020/1/23

Y1 - 2020/1/23

N2 - Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets. Using a probe analog of the antimalarial natural product Sal A, Yoo et al. identify its targets as multiple essential serine hydrolases, including a homolog of human monoacylglycerol lipase. Because parasites were unable to generate robust in vitro resistance to Sal A, these enzymes represent promising targets for antimalarial drugs.

AB - Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets. Using a probe analog of the antimalarial natural product Sal A, Yoo et al. identify its targets as multiple essential serine hydrolases, including a homolog of human monoacylglycerol lipase. Because parasites were unable to generate robust in vitro resistance to Sal A, these enzymes represent promising targets for antimalarial drugs.

KW - activity-based probes

KW - chemical proteomics

KW - lipid metabolism

KW - malaria

KW - natural products

KW - Plasmodium falciparum

KW - Salinipostin A

KW - serine hydrolases

UR - https://www.scopus.com/pages/publications/85079357670

UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027986/

U2 - 10.1016/j.chembiol.2020.01.001

DO - 10.1016/j.chembiol.2020.01.001

M3 - Article

C2 - 31978322

AN - SCOPUS:85079357670

SN - 2451-9456

VL - 27

SP - 143

EP - 157

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 2

ER -

The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites

Abstract

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Keywords

ASJC Scopus subject areas

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