Dimerization of Arginyl-tRNA Synthetase by Free Heme Drives Its Inactivation in Plasmodium falciparum

Abstract

Excess cellular heme is toxic, and malaria parasites regulate its levels during hemoglobin digestion. Aminoacyl-tRNA synthetases are ubiquitous enzymes, and of these, arginyl-tRNA synthetase (RRS) is unique as its enzymatic product of charged tRNA is required for protein synthesis and degradation. We show that Plasmodium falciparum arginyl-tRNA synthetase (PfRRS) is an active, cytosolic, and monomeric enzyme. Its high-resolution crystal structure highlights critical structural differences with the human enzyme. We further show that hemin binds to and inhibits the aminoacylation activity of PfRRS.Hemin induces a dimeric form of PfRRS thatis thusrendered enzymatically dead as it is unable torecognize its cognate tRNA(arg). Excessive hemin inchloroquine-treated malaria parasites results in significantly reduced charged tRNA(arg) levels, thussuggesting deceleration of protein synthesis. Thesedata together suggest that the inhibition ofPlasmodium falciparum arginyl-tRNA synthetase can now be synergized with existing antimalarials for more potent drug cocktails against malaria parasites.