PXD014313

PXD014313 is an original dataset announced via ProteomeXchange.

Title	System-wide biochemical analysis reveals ozonide and artemisinin antimalarials initially act by disrupting malaria parasite haemoglobin digestion
Description	Artemisinins are currently the first-line antimalarials, and rely on a peroxide pharmacophore for their potent activity. OZ277 (arterolane) and OZ439 (artefenomel) are newer synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of peroxide-treated P. falciparum infected red blood cells (iRBCs) revealed a rapid depletion of short Hb-derived peptides, while untargeted peptidomics showed accumulation of longer Hb peptides. Quantitative proteomics and ABPP assays demonstrated that Hb digesting proteases were significantly increased in abundance and activity following treatment, respectively. The association between peroxide activity and Hb catabolism was also confirmed in a K13-mutant artemisinin resistant parasite line. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in peroxide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short peroxide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate peroxide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage peroxide-induced damage.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:04:22.547.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ghizal Siddiqui
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606; scientific name: Plasmodium falciparum (isolate 3D7); NCBI TaxID: 36329;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-06-20 02:03:32	ID requested
1	2020-05-25 03:42:23	announced
2	2020-08-11 05:57:07	announced	2020-08-11: Updated publication reference for PubMed record(s): 32589689.
⏵ 3	2024-10-22 05:04:23	announced	2024-10-22: Updated project metadata.

10.1371/journal.ppat.1008485;

Giannangelo C, Siddiqui G, De Paoli A, Anderson BM, Edgington-Mitchell LE, Charman SA, Creek DJ, System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion. PLoS Pathog, 16(6):e1008485(2020) [pubmed]

submitter keyword: Metabolomics, Peptidomics,Peroxide antimalarial, Malaria, Proteomics, Plasmodium falciparum

Darren Creek
contact affiliation	Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, Parkville, Victoria Australia.
contact email	darren.creek@monash.edu
lab head
Ghizal Siddiqui
contact affiliation	Monash University
contact email	ghizal.siddiqui@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014313
     1. Label: PRIDE project
     2. Name: System-wide biochemical analysis reveals ozonide and artemisinin antimalarials initially act by disrupting malaria parasite haemoglobin digestion