Weerapana E

References (4)

Title : Characterization of Serine Hydrolases Across Clinical Isolates of Commensal Skin Bacteria Staphylococcus epidermidis Using Activity-Based Protein Profiling - Keller_2020_ACS.Infect.Dis_6_930
Author(s) : Keller LJ , Lentz CS , Chen YE , Metivier RJ , Weerapana E , Fischbach MA , Bogyo M
Ref : ACS Infect Dis , 6 :930 , 2020
Abstract : The bacterial genus Staphylococcus comprises diverse species that colonize the skin as commensals but can also cause infection. Previous work identified a family of serine hydrolases termed fluorophoshonate-binding hydrolases (Fphs) in the pathogenic bacteria Staphylococcus aureus, one of which, FphB, functions as a virulence factor. Using a combination of bioinformatics and activity-based protein profiling (ABPP), we identify homologues of these enzymes in the related commensal bacteria Staphylococcus epidermidis. Two of the S. aureus Fph enzymes were not identified in S. epidermidis. Using ABPP, we identified several candidate hydrolases that were not previously identified in S. aureus that may be functionally related to the Fphs. Interestingly, the activity of the Fphs vary across clinical isolates of S. epidermidis. Biochemical characterization of the FphB homologue in S. epidermidis (SeFphB) suggests it is a functional homologue of FphB in S. aureus, but our preliminary studies suggest it may not have a role in colonization in vivo. This potential difference in biological function between the Fphs of closely related staphylococcal species may provide mechanisms for specific inhibition of S. aureus infection without perturbing commensal communities of related bacteria.
ESTHER : Keller_2020_ACS.Infect.Dis_6_930
PubMedSearch : Keller_2020_ACS.Infect.Dis_6_930
PubMedID: 32298574
Gene_locus related to this paper: staep-GEHD , staep-lipas , staep-SE0226 , staep-SE0245 , staep-SE0424 , staep-SE0564 , staep-SE0714 , staep-SE0980 , staep-SE1460 , staep-SE1780 , staep-SERP2035 , staep-SE2095 , staep-SE2213 , staep-SE2328 , staep-SE2403

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

Title : Identification of a S. aureus virulence factor by activity-based protein profiling (ABPP) - Lentz_2018_Nat.Chem.Biol_14_609
Author(s) : Lentz CS , Sheldon JR , Crawford LA , Cooper R , Garland M , Amieva MR , Weerapana E , Skaar EP , Bogyo M
Ref : Nat Chemical Biology , 14 :609 , 2018
Abstract : Serine hydrolases play diverse roles in regulating host-pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen Staphylococcus aureus. Here we describe a chemical proteomic screen that identified ten previously uncharacterized S. aureus serine hydrolases that mostly lack human homologs. We termed these enzymes fluorophosphonate-binding hydrolases (FphA-J). One hydrolase, FphB, can process short fatty acid esters, exhibits increased activity in response to host cell factors, is located predominantly on the bacterial cell surface in a subset of cells, and is concentrated in the division septum. Genetic disruption of fphB confirmed that the enzyme is dispensable for bacterial growth in culture but crucial for establishing infection in distinct sites in vivo. A selective small molecule inhibitor of FphB effectively reduced infectivity in vivo, suggesting that it may be a viable therapeutic target for the treatment or management of Staphylococcus infections.
ESTHER : Lentz_2018_Nat.Chem.Biol_14_609
PubMedSearch : Lentz_2018_Nat.Chem.Biol_14_609
PubMedID: 29769740
Gene_locus related to this paper: staau-MW2456 , staau-SA2422

Title : Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion - Child_2013_Nat.Chem.Biol_9_651
Author(s) : Child MA , Hall CI , Beck JR , Ofori LO , Albrow VE , Garland M , Bowyer PW , Bradley PJ , Powers JC , Boothroyd JC , Weerapana E , Bogyo M
Ref : Nat Chemical Biology , 9 :651 , 2013
Abstract : Although there have been numerous advances in our understanding of how apicomplexan parasites such as Toxoplasma gondii enter host cells, many of the signaling pathways and enzymes involved in the organization of invasion mediators remain poorly defined. We recently performed a forward chemical-genetic screen in T. gondii and identified compounds that markedly enhanced infectivity. Although molecular dissection of invasion has benefited from the use of small-molecule inhibitors, the mechanisms underlying induction of invasion by small-molecule enhancers have never been described. Here we identify the Toxoplasma ortholog of human APT1, palmitoyl protein thioesterase-1 (TgPPT1), as the target of one class of small-molecule enhancers. Inhibition of this uncharacterized thioesterase triggered secretion of invasion-associated organelles, increased motility and enhanced the invasive capacity of tachyzoites. We demonstrate that TgPPT1 is a bona fide depalmitoylase, thereby establishing an important role for dynamic and reversible palmitoylation in host-cell invasion by T. gondii.
ESTHER : Child_2013_Nat.Chem.Biol_9_651
PubMedSearch : Child_2013_Nat.Chem.Biol_9_651
PubMedID: 23934245
Gene_locus related to this paper: toxgo-s4ug63