The role of Plasmodium falciparum acyl-coenzyme A synthetase 10 in fatty acid acquisition and lipid synthesis
- 1Virginia Polytechnic Institute and State University
Abstract
During the asexual blood stage, malaria parasites synthesize large quantities of lipids to support their rapid proliferation. Exogenous fatty acids obtained from host plasma are activated for lipid synthesis by parasite acyl-coenzyme A synthetases (ACSs). Of the twelve Plasmodium falciparum ACS homologs, ACS10 has emerged as a key blood-stage enzyme. Here, we sought to define the role of ACS10 in fatty acid acquisition and lipid synthesis during asexual development. To accomplish this, we have employed fatty acid alkyne probes of parasite lipid synthesis together with selective depletion of ACS10 in a conditional knockdown parasite line. This approach revealed that ACS10 is required for efficient incorporation of 16- to 20-carbon unsaturated fatty acid alkynes and a 20-carbon, saturated fatty acid alkyne into the major parasite phospholipids and neutral lipids. In contrast, shorter saturated fatty acid alkynes were either unaffected by ACS10 depletion or were hyper-incorporated into parasite lipids. ACS10 knockdown elicited a profound deformation of the food vacuole, which was likely caused by an imbalance of saturated and unsaturated fatty acids in parasite lipids. To promote the discovery and characterization of ACS inhibitors, we have established a fatty acid alkyne-based approach for identifying compounds that target ACS10 as their primary mode of action.
Related
- Nuclear acetyl-CoA production by acetyl-CoA synthetase enables dynamic histone acetylation and gene expression in Plasmodium falciparum
- Potent reaction hijacking inhibitors of Plasmodium falciparum asparagine tRNA synthetase
- A Plasmodium falciparum Pangenome Resource to Drive Structural Variant Discovery and to assist Malaria Control
- Leave-One-Out-Cross-Validation Based Machine Learning Algorithms for Efficient, Scalable, and Robust Prediction of Artemisinin Resistance in Plasmodium falciparum Kelch13 mutants.
- Chemoproteomic profiling of Plasmodium falciparum Hsp90 inhibition reveals functional link to DNA replication pathways
BibTeX
@misc{fike2026role,
title = {{The role of Plasmodium falciparum acyl-coenzyme A synthetase 10 in fatty acid acquisition and lipid synthesis}},
author = {K. R. Fike and H. Santos and M. Klemba},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.06.764794},
url = {https://www.biorxiv.org/content/10.64898/2026.11.06.764794v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The role of Plasmodium falciparum acyl-coenzyme A synthetase 10 in fatty acid acquisition and lipid synthesis
AU - K. R. Fike
AU - H. Santos
AU - M. Klemba
PY - 2026
DA - 2026/11/06
PB - bioRxiv
DO - 10.64898/2026.11.06.764794
UR - https://www.biorxiv.org/content/10.64898/2026.11.06.764794v1
AB - During the asexual blood stage, malaria parasites synthesize large quantities of lipids to support their rapid proliferation. Exogenous fatty acids obtained from host plasma are activated for lipid synthesis by parasite acyl-coenzyme A synthetases (ACSs). Of the twelve Plasmodium falciparum ACS homologs, ACS10 has emerged as a key blood-stage enzyme. Here, we sought to define the role of ACS10 in fatty acid acquisition and lipid synthesis during asexual development. To accomplish this, we have employed fatty acid alkyne probes of parasite lipid synthesis together with selective depletion of ACS10 in a conditional knockdown parasite line. This approach revealed that ACS10 is required for efficient incorporation of 16- to 20-carbon unsaturated fatty acid alkynes and a 20-carbon, saturated fatty acid alkyne into the major parasite phospholipids and neutral lipids. In contrast, shorter saturated fatty acid alkynes were either unaffected by ACS10 depletion or were hyper-incorporated into parasite lipids. ACS10 knockdown elicited a profound deformation of the food vacuole, which was likely caused by an imbalance of saturated and unsaturated fatty acids in parasite lipids. To promote the discovery and characterization of ACS inhibitors, we have established a fatty acid alkyne-based approach for identifying compounds that target ACS10 as their primary mode of action.
ER -