Cieplak P

References (2)

Title : Toxoplasma gondii serine hydrolases regulate parasite lipid mobilization during growth and replication within the host - Onguka_2021_Cell.Chem.Biol__
Author(s) : Onguka O , Babin BM , Lakemeyer M , Foe IT , Amara N , Terrell SM , Lum KM , Cieplak P , Niphakis MJ , Long JZ , Bogyo M
Ref : Cell Chemical Biology , : , 2021
Abstract : The intracellular protozoan parasite Toxoplasma gondii must scavenge cholesterol and other lipids from the host to facilitate intracellular growth and replication. Enzymes responsible for neutral lipid synthesis have been identified but there is no evidence for enzymes that catalyze lipolysis of cholesterol esters and esterified lipids. Here, we characterize several T. gondii serine hydrolases with esterase and thioesterase activities that were previously thought to be depalmitoylating enzymes. We find they do not cleave palmitoyl thiol esters but rather hydrolyze short-chain lipid esters. Deletion of one of the hydrolases results in alterations in levels of multiple lipids species. We also identify small-molecule inhibitors of these hydrolases and show that treatment of parasites results in phenotypic defects reminiscent of parasites exposed to excess cholesterol or oleic acid. Together, these data characterize enzymes necessary for processing lipids critical for infection and highlight the potential for targeting parasite hydrolases for therapeutic applications.
ESTHER : Onguka_2021_Cell.Chem.Biol__
PubMedSearch : Onguka_2021_Cell.Chem.Biol__
PubMedID: 34043961
Gene_locus related to this paper: toxgo-TgASH3 , toxgo-TgASH2 , toxgo-s4ug63 , toxgo-a0a125yz56

Title : The Antimalarial Natural Product Salinipostin A Identifies Essential alpha\/beta Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites - Yoo_2020_Cell.Chem.Biol_27_143
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
Ref : Cell Chemical Biology , 27 :143 , 2020
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.
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