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 - http://www.scopus.com/inward/record.url?scp=85079357670&partnerID=8YFLogxK
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 -
