Dataset Information

The Golgi stacking protein GRASP55 represents an effector protein of the natural compound Prodigiosin

ABSTRACT: The bacterial secondary metabolite prodigiosin has been shown to exert anticancer, antimalarial, antibacterial and immunomodulatory properties. With regard to cancer, it has been reported that it affects tumor cells but not non-malignant cells, making it a promising lead compound for anticancer drug discovery. However, a direct protein target has not yet been experimentally identified. Here, we identify the Golgi stacking protein GRASP55 as effector target protein of prodigiosin and found evidence that GRASP55 knockout cells show an altered pattern on secreted proteins upon prodigionsin treatment.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Gereon Poschmann

LAB HEAD: Gereon Poschmann

PROVIDER: PXD042909 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

The Golgi stacking protein GRASP55 is targeted by the natural compound prodigiosin.

Berning Lena L Lenz Thomas T Bergmann Ann Kathrin AK Poschmann Gereon G Brass Hannah U C HUC Schlütermann David D Friedrich Annabelle A Mendiburo María José MJ David Céline C Akgün Seda S Pietruszka Jörg J Stühler Kai K Stork Björn B

Cell communication and signaling : CCS 20231005 1

<h4>Background</h4>The bacterial secondary metabolite prodigiosin has been shown to exert anticancer, antimalarial, antibacterial and immunomodulatory properties. With regard to cancer, it has been reported to affect cancer cells but not non-malignant cells, rendering prodigiosin a promising lead compound for anticancer drug discovery. However, a direct protein target has not yet been experimentally identified.<h4>Methods</h4>We used mass spectrometry-based thermal proteome profiling in order to ...[more]

PMID: 37798768

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Project description:The increasing incidence of antimalarial drug resistance to the first-line artemisinins, and their combination partner drugs, underpins an urgent need for new antimalarial drugs, ideally with a novel mechanism of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum, low cytotoxicity, potent in vivo efficacy against murine malaria, and favourable preclinical pharmacokinetics, including a lengthy plasma elimination half-life. This study demonstrates the application of a “multi-omics” workflow based on high resolution orbitrap mass spectrometry to investigate the impact of JPC-3210 on biochemical pathways within P. falciparum infected red blood cells. Metabolomics and peptidomics analysis revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a depletion in short hemoglobin-derived peptides, while peptidomics analysis showed a depletion in longer hemoglobin-derived peptides. In order to further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerisation assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerisation, about 10-fold less potent then the quinoline antimalarials. Furthermore, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature in comparison to other known antimalarials. Whilst JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. In conclusion, multi-omics studies using high resolution mass spectrometry revealed JPC-3210 to possess a unique mechanism of action involving inhibition of hemoglobin digestion, depletion of DNA replication and synthesis proteins, and elevation of regulators of protein translation. Importantly, this mechanism is distinct from currently-used antimalarials, suggesting that JPC-3210 warrants further investigation as a potentially useful new antimalarial agent.

Dataset Information

The Golgi stacking protein GRASP55 represents an effector protein of the natural compound Prodigiosin

Publications

The Golgi stacking protein GRASP55 is targeted by the natural compound prodigiosin.

Similar Datasets

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