(Below N is a link to NCBI taxonomic web page and E link to ESTHER at designed phylum.) > cellular organisms: NE > Eukaryota: NE > Alveolata: NE > Apicomplexa: NE > Aconoidasida: NE > Haemosporida: NE > Plasmodiidae: NE > Plasmodium: NE > Plasmodium (Laverania): NE > Plasmodium falciparum: NE
LegendThis sequence has been compared to family alignement (MSA) red => minority aminoacid blue => majority aminoacid color intensity => conservation rate title => sequence position(MSA position)aminoacid rate Catalytic site Catalytic site in the MSA MYNYYMNVVNSFFNTKKDDNNNNNNILEYNAHKEKYFYTDRMNFDEMSSF LLKKLKNTNIGKKNDIMFVAHSMGGLLTQYILLKNDHFLNKTKCIFFYAT PHFGSPLSSSAYLLKPFLSPYVYQLNDYDSKLNYLQQSFKERIKNKDLVI YSFSESEKSPLPFIGVYTMIVPCTSAYLYYSKIFTIIKYCNHLEISKLNS EEDVKFYYLNKVMKEFSKIK
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.
