title: 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 that is thus rendered enzymatically dead as it is unable to recognize its cognate tRNA(arg). Excessive hemin in chloroquine-treated malaria parasites results in significantly reduced charged tRNA(arg) 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.
authors: Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors: Vitul
authors: V
authors: Jain
authors: Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors: Manickam
authors: M
authors: Yogavel
authors: Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India. Electronic address: amit.icgeb@gmail.com.
authors: Amit
authors: A
authors: Sharma
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000737:chemistry* / Q000378:metabolism; D001126:Arginine-tRNA Ligase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015870:Gene Expression; D006418:Heme / Q000737:chemistry* / Q000494:pharmacology; D006427:Hemin / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012347:RNA, Transfer, Arg / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D012347:RNA, Transfer, Arg; D011994:Recombinant Proteins; D006418:Heme; D006427:Hemin; D002738:Chloroquine; D001120:Arginine; D001126:Arginine-tRNA Ligase