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The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.

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 α/β 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.

SUBMITTER: Yoo E

PROVIDER: S-EPMC8027986 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The antimalarial natural product salinipostin A identifies essential alpha/beta serine hydrolases involved in lipid metabolism in P. falciparum parasites

Project description:Salinipostin A (Sal A) is a bicyclic phosphotriester natural product isolated from the marine bacterium Salinospora sp. that exhibits potent antimalarial activity. However, the direct targets and mechanisms by which it exerts its effects are poorly understood. Here, we use semi-synthesis to generate a Sal A-derived activity-based probe, enabling the identification of its targets in the human malaria parasite Plasmodium falciparum. All of the identified proteins contain an / serine hydrolase domain and several have been reported as essential for growth of the parasite. One of the essential targets is an uncharacterized protein (PF3D7_1038900, referred to as PfMAGLLP) that displays a high degree of homology to human monoacylglycerol lipase (MAGL). Recombinant expression of this protein confirms that it processes lipid esters as well as a bona fide MAGL acylglyceride substrate. PfMAGLLP is potently inhibited by Sal A, as well as by human MAGL inhibitors and by the anti-obesity drug Orlistat that disrupts lipid metabolism and induces a similar death phenotype in parasites as Sal A. Resistance selection studies with Sal A yielded parasites that showed only a mild reduction in sensitivity. Multiple whole-genome sequenced Sal A-selected clones displayed nonsynonymous mutations in a gene coding for a putative PRELI domain-containing protein (PF3D7_1324400) related to a mitochondrial protein linked to multidrug resistance in Toxoplasma gondii. Together, these data suggest that the antimalarial activity of Sal A results from inhibition of multiple essential serine hydrolases, leading to disruption of lipid metabolism pathways. The combination of the non-essentiality of many of these serine hydrolases in humans and the lack of parasite resistance pathways to fully overcome inhibitor treatment suggest that this class of enzymes represent promising targets for development of next-generation antimalarial agents.

2020-01-24 | PXD016835 | Pride

Functional annotation of serine hydrolases in the asexual erythrocytic stage of Plasmodium falciparum.

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Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets

Project description:Malaria, caused by Plasmodium falciparum, remains a significant health burden. The barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that Salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance. Given the difficulty of employing natural products as therapeutic agents, we synthesized a small library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled the identification of therapeutically relevant targets. We also confirm that this compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor, Orlistat. In addition, like SalA, our compound induces only weak resistance, attributable to mutations in a single protein involved in multidrug resistance. These data suggest that mixed alkyl/aryl phosphonates are a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.

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A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation.

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The expanding diversity of serine hydrolases.

Project description:Serine hydrolases use a hydroxyl of a serine, assisted by one or more other residues, to cleave peptide bonds. They belong to several different families whose general mechanism is well known. However, the subtle structural differences that have recently been observed across a variety of families shed light on their functional diversity, including variations in mechanism of action, differences in the modes of substrate binding, and substrate-assisted orientation of catalytic residues. Of particular interest are the Rhomboid family serine proteinases that are active within the plasma membrane, for which several new structures have been reported. Because these enzymes are involved in biological and pathological processes, many are becoming important targets of drug design.

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2020-11-30 | GSE156685 | GEO

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