Family Report for: Plasmodium_subtelomeric_PST-A

These proteins represent a paralogous family of genes found in Plasmodium falciparum and Plasmodium yoelii that are closely related to various phospholipases and lysophospholipases of plants as well as generally being related to the alpha/beta-fold superfamily of hydrolases. These genes are preferentially located in the subtelomeric regions of the chromosomes of both P. falciparum and P. yoelii. TIGRFAMs TIGR01607 (PST-A). Close sequences of other Apicomplexa species were included

Title: The Antimalarial Natural Product Salinipostin A Identifies Essential alpha/beta Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites
Yoo E, Schulze CJ, Stokes BH, Onguka O, Yeo T, Mok S, Gnadig NF, Zhou Y, Kurita K and Bogyo M <11 more author(s)> Yoo E, Schulze CJ, Stokes BH, Onguka O, Yeo T, Mok S, Gnadig 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 (- 11)
Ref: Cell Chemical Biology, 27:143, 2020 : PubMed
Abstract


ESTHER: Yoo_2020_Cell.Chem.Biol_27_143
PubMedSearch: Yoo 2020 Cell.Chem.Biol 27 143
PubMedID: 31978322
Gene_locus related to this paper: plaf7-q8ii19, plafa-a0a143zya4, plaf7-q8iik5, plafa-MAL8P1.38, plafa-PF07.0040, plafa-PF10.0020, plafa-PF10.0379, plafa-PF13.0153
Inhibitor(s) related to this paper: MJN110, JW651, KML29, Sal-A-alkyne, Salinipostin-A, Orlistat

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 alpha/beta 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.