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标题：Activity-based protein profiling of human and plasmodium serine hydrolases and interrogation of potential antimalarial targets
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作者：Dara Davison ; Steven Howell ; Ambrosius P. Snijders 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：9
页码：1-31
DOI：10.1016/j.isci.2022.104996
语种：English
出版社：Elsevier
摘要：SummaryMalaria remains a global health issue requiring the identification of novel therapeutic targets to combat drug resistance. Metabolic serine hydrolases are druggable enzymes playing essential roles in lipid metabolism. However, very few have been investigated in malaria-causing parasites. Here, we used fluorophosphonate broad-spectrum activity-based probes and quantitative chemical proteomics to annotate and profile the activity of more than half of predicted serine hydrolases inP.falciparumacross the erythrocytic cycle. Using conditional genetics, we demonstrate that the activities of four serine hydrolases, previously annotated as essential (or important) in genetic screens, are actually dispensable for parasite replication. Of importance, we also identified eight human serine hydrolases that are specifically activated at different developmental stages. Chemical inhibition of two of them blocks parasite replication. This strongly suggests that parasites co-opt the activity of host enzymes and that this opens a new drug development strategy against which the parasites are less likely to develop resistance.Graphical abstractDisplay OmittedHighlights•P.falciparumhas 48 predicted metabolic SHs. Many react with the ABP, FP-N3•The activity of 25PfSHs and 8HsSHs was profiled throughout the asexual life cycle•Catalytic mutants of 4PfSHs (formerly held essential) had no parasite growth effect•Selective inhibitors for 2HsSHs (APEH and LPLA2) affected parasite growthClinical microbiology; Medical biochemistry; Proteomics