Structural highlights
Publication Abstract from PubMedExcess 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 that is thus rendered enzymatically dead as it is unable to recognize its cognate tRNAarg. Excessive hemin in chloroquine-treated malaria parasites results in significantly reduced charged tRNAarg levels, thus suggesting deceleration of protein synthesis. These data together suggest that the inhibition of Plasmodium falciparum arginyl-tRNA synthetase can now be synergized with existing antimalarials for more potent drug cocktails against malaria parasites. Dimerization of Arginyl-tRNA Synthetase by Free Heme Drives Its Inactivation in Plasmodium falciparum.,Jain V, Yogavel M, Sharma A Structure. 2016 Sep 6;24(9):1476-1487. doi: 10.1016/j.str.2016.06.018. Epub 2016 , Aug 5. PMID:27502052[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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