Summary of Study ST001239

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000829. The data can be accessed directly via it's Project DOI: 10.21228/M8HX2M This work is supported by NIH grant, U2C- DK119886.

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Study IDST001239
Study TitleNMR assignment of synthetic pantothenamides (part-II)
Study Summary1H and 13C NMR of synthesized pantothenamides used for in vitro metabolomics studies.
Institute
Pennsylvania State University
Last NameLlinás
First NameManuel
AddressW126 Millennium Science Complex, University Park, PENNSYLVANIA, 16802, USA
Emailmul27@psu.edu
Phone(814) 867-3527
Submit Date2019-08-08
Raw Data AvailableYes
Raw Data File Type(s)fid
Analysis Type DetailNMR
Release Date2019-09-23
Release Version1
Manuel Llinás Manuel Llinás
https://dx.doi.org/10.21228/M8HX2M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000829
Project DOI:doi: 10.21228/M8HX2M
Project Title:Antimalarial pantothenamide metabolites target acetyl-CoA biosynthesis in Plasmodium falciparum
Project Summary:Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report the discovery of potent pantothenamide bioisosteres that are active against blood-stage Plasmodium falciparum parasites and that block transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties and cleared parasites in a humanized mouse infection model of P. falciparum. Metabolomics revealed that CoA biosynthetic enzymes converted pantothenamides into CoA-analogs that interfered with parasite acetyl-CoA anabolism. In vitro generated resistant parasites showed mutations in acetyl-CoA synthetase and acyl-CoA synthetase 11. Introduction and reversion of these mutations in P. falciparum by CRISPR/Cas9 gene editing confirmed the key roles of these enzymes in the sensitivity of the malaria parasite to pantothenamides. These pantothenamide compounds with a unique mode of action may have potential as drugs against malaria parasites.
Institute:Pennsylvania State University
Last Name:Llinás
First Name:Manuel
Address:W126 Millennium Science Complex, University Park, PENNSYLVANIA, 16802, USA
Email:mul27@psu.edu
Phone:(814) 867-3527
Publications:https://stm.sciencemag.org/content/11/510/eaas9917 DOI: 10.1126/scitranslmed.aas9917

Subject:

Subject ID:SU001307
Subject Type:Other
Subject Species:Synthetic

Factors:

Subject type: Other; Subject species: Synthetic (Factor headings shown in green)

mb_sample_id local_sample_id Spectra
SA089903052_13C13C NMR
SA089904258_13C13C NMR
SA089905026_13C13C NMR
SA089906968_13C13C NMR
SA089907006_13C13C NMR
SA089908017_13C13C NMR
SA089909968_1H1H NMR
SA089910258_1H1H NMR
SA089911052_1H1H NMR
SA089912017_1H1H NMR
SA089913026_1H1H NMR
SA089914006_1H1H NMR
SA089915052_HSQCHSQC NMR
Showing results 1 to 13 of 13

Collection:

Collection ID:CO001301
Collection Summary:Synthesized compounds were freeze dried and resuspended in MeOD between 10-20mM. Samples were then placed into NMR sample tubes for analysis.
Sample Type:Synthetic chemistry

Treatment:

Treatment ID:TR001322
Treatment Summary:No treatment, these synthetic compounds tested for structure accuracy and purity.

Sample Preparation:

Sampleprep ID:SP001315
Sampleprep Summary:Several of the original synthesized compounds were in DMSO. This was removed, to the best of our ability, using a freeze dryer before dissolving in MeOD.

Analysis:

Analysis ID:AN002058
Analysis Type:NMR
Num Factors:3

NMR:

NMR ID:NM000152
Analysis ID:AN002058
Instrument Name:Bruker AVIII-HD-500
Instrument Type:FT-NMR
NMR Experiment Type:Other
Spectrometer Frequency:500 MHz
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