Summary of project PR002663
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 PR002663. The data can be accessed directly via it's Project DOI: 10.21228/M8F545 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002663 |
| Project DOI: | doi: 10.21228/M8F545 |
| Project Title: | Loss of P. falciparum Amino Acid Transporter (ApiAT2) Function Increases Intracellular Proline and Confers Resistance to Prolyl-tRNA Synthetase Inhibitors |
| Project Summary: | Plasmodium falciparum evades the antimalarial activity of proline-competitive prolyl-tRNA synthetase (PfProRS) inhibitors, such as halofuginone (HFG), by a unique resistance mechanism termed the Adaptive Proline Response (APR). The APR is characterized by a marked elevation of intracellular proline following drug exposure. Contrary to initial expectations, the APR is not mediated by alterations in canonical proline metabolic pathways involving arginase (PfARG) and ornithine aminotransferase (PfOAT). Instead, we identified loss-of-function mutations in the Apicomplexan Amino acid Transporter 2 (PfApiAT2) as the primary genetic driver of this resistance phenotype. Importantly, reversion of these mutations to wildtype effectively suppresses the APR, establishing PfApiAT2 as the molecular determinant of this novel resistance mechanism. The elucidation of the APR significantly advances our understanding of antimalarial drug resistance. By delineating the role of PfApiAT2 in this process, we establish critical insights for the development of strategies to circumvent PfProRS inhibitor resistance for future antimalarial therapies. |
| Institute: | Broad Institute of MIT and Harvard |
| Department: | Metabolomics Platform |
| Last Name: | Clish |
| First Name: | Clary |
| Address: | 300 Binney Street, Cambridge, MA, 02142, USA |
| Email: | clary@broadinstitute.org |
| Phone: | 617-714-7654 |
| Funding Source: | NIH-NIAID R01AI143723 and R21AI132981; NIH-NIGMS T32 GM008666 and F31AI129412; Bill and Melinda Gates Foundation OPP1132451 and OPP1086203; and the Harvard Defeating Malaria Initiative |
| Project Comments: | 5 experiements |
| Contributors: | Selina Bopp, Lọla Fagbami, Amy Deik, Claudia Taccheri, Akansha Pant, Madeline Luth, Daisy Chen, Mark A. Tye, Imran Ullah, Robert Morris, Wilhelm Haas, Elizabeth A. Winzeler, Clary B. Clish, Amanda K. Lukens, Ralph Mazitschek, Dyann F. Wirth |
Summary of all studies in project PR002663
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST004222 | Elucidating the source of elevated proline in APR parasites | Plasmodium falciparum | Broad Institute of MIT and Harvard | MS | 2025-10-07 | 1 | 7 | Uploaded data (1.1G)* |
| ST004233 | Validating the role of the arginine to proline biosynthetic pathway in the APR | Plasmodium falciparum | Broad Institute of MIT and Harvard | MS | 2025-10-07 | 1 | 24 | Uploaded data (3.9G)* |
| ST004239 | Labeled amino acid uptake from multiplexed isotope media | Plasmodium falciparum | Broad Institute of MIT and Harvard | MS | 2025-10-07 | 1 | 72 | Uploaded data (20.3G)* |
| ST004240 | PfApiAT2 loss of function leads to Adaptive Proline Response (APR) | Plasmodium falciparum | Broad Institute of MIT and Harvard | MS | 2025-10-06 | 1 | 30 | Uploaded data (3.3G)* |
| ST004244 | Parasites with a disrupted arginine to proline pathway can still mount an APR | Plasmodium falciparum | Broad Institute of MIT and Harvard | MS | 2025-10-06 | 1 | 36 | Uploaded data (4.8G)* |
