Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum
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. W...
| Príomhchruthaitheoirí: | , , |
|---|---|
| Formáid: | Journal article |
| Foilsithe / Cruthaithe: |
Cell Press
2016
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| _version_ | 1826282318424178688 |
|---|---|
| author | Jain, V Yogavel, M Sharma, A |
| author_facet | Jain, V Yogavel, M Sharma, A |
| author_sort | Jain, V |
| collection | OXFORD |
| description | 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 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. |
| first_indexed | 2024-03-07T00:42:02Z |
| format | Journal article |
| id | oxford-uuid:835eff8b-2004-490b-bf1c-3da8f1c8e8f1 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T00:42:02Z |
| publishDate | 2016 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:835eff8b-2004-490b-bf1c-3da8f1c8e8f12022-03-26T21:43:45ZDimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparumJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:835eff8b-2004-490b-bf1c-3da8f1c8e8f1Symplectic Elements at OxfordCell Press2016Jain, VYogavel, MSharma, AExcess 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. |
| spellingShingle | Jain, V Yogavel, M Sharma, A Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum |
| title | Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum |
| title_full | Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum |
| title_fullStr | Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum |
| title_full_unstemmed | Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum |
| title_short | Dimerization of arginyl-tRNA synthetase by free heme drives its inactivation in plasmodium falciparum |
| title_sort | dimerization of arginyl trna synthetase by free heme drives its inactivation in plasmodium falciparum |
| work_keys_str_mv | AT jainv dimerizationofarginyltrnasynthetasebyfreehemedrivesitsinactivationinplasmodiumfalciparum AT yogavelm dimerizationofarginyltrnasynthetasebyfreehemedrivesitsinactivationinplasmodiumfalciparum AT sharmaa dimerizationofarginyltrnasynthetasebyfreehemedrivesitsinactivationinplasmodiumfalciparum |