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The dUTPase Enzyme Is Essential in Mycobacterium smegmatis
Thymidine biosynthesis is essential in all cells. Inhibitors of the enzymes involved in this pathway (e.g. methotrexate) are thus frequently used as cytostatics. Due to its pivotal role in mycobacterial thymidylate synthesis dUTPase, which hydrolyzes dUTP into the dTTP precursor dUMP, has been sugge...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360063/ https://www.ncbi.nlm.nih.gov/pubmed/22655049 http://dx.doi.org/10.1371/journal.pone.0037461 |
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author | Pecsi, Ildiko Hirmondo, Rita Brown, Amanda C. Lopata, Anna Parish, Tanya Vertessy, Beata G. Tóth, Judit |
author_facet | Pecsi, Ildiko Hirmondo, Rita Brown, Amanda C. Lopata, Anna Parish, Tanya Vertessy, Beata G. Tóth, Judit |
author_sort | Pecsi, Ildiko |
collection | PubMed |
description | Thymidine biosynthesis is essential in all cells. Inhibitors of the enzymes involved in this pathway (e.g. methotrexate) are thus frequently used as cytostatics. Due to its pivotal role in mycobacterial thymidylate synthesis dUTPase, which hydrolyzes dUTP into the dTTP precursor dUMP, has been suggested as a target for new antitubercular agents. All mycobacterial genomes encode dUTPase with a mycobacteria-specific surface loop absent in the human dUTPase. Using Mycobacterium smegmatis as a fast growing model for Mycobacterium tuberculosis, we demonstrate that dUTPase knock-out results in lethality that can be reverted by complementation with wild-type dUTPase. Interestingly, a mutant dUTPase gene lacking the genus-specific loop was unable to complement the knock-out phenotype. We also show that deletion of the mycobacteria-specific loop has no major effect on dUTPase enzymatic properties in vitro and thus a yet to be identified loop-specific function seems to be essential within the bacterial cell context. In addition, here we demonstrated that Mycobacterium tuberculosis dUTPase is fully functional in Mycobacterium smegmatis as it rescues the lethal knock-out phenotype. Our results indicate the potential of dUTPase as a target for antitubercular drugs and identify a genus-specific surface loop on the enzyme as a selective target. |
format | Online Article Text |
id | pubmed-3360063 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33600632012-05-31 The dUTPase Enzyme Is Essential in Mycobacterium smegmatis Pecsi, Ildiko Hirmondo, Rita Brown, Amanda C. Lopata, Anna Parish, Tanya Vertessy, Beata G. Tóth, Judit PLoS One Research Article Thymidine biosynthesis is essential in all cells. Inhibitors of the enzymes involved in this pathway (e.g. methotrexate) are thus frequently used as cytostatics. Due to its pivotal role in mycobacterial thymidylate synthesis dUTPase, which hydrolyzes dUTP into the dTTP precursor dUMP, has been suggested as a target for new antitubercular agents. All mycobacterial genomes encode dUTPase with a mycobacteria-specific surface loop absent in the human dUTPase. Using Mycobacterium smegmatis as a fast growing model for Mycobacterium tuberculosis, we demonstrate that dUTPase knock-out results in lethality that can be reverted by complementation with wild-type dUTPase. Interestingly, a mutant dUTPase gene lacking the genus-specific loop was unable to complement the knock-out phenotype. We also show that deletion of the mycobacteria-specific loop has no major effect on dUTPase enzymatic properties in vitro and thus a yet to be identified loop-specific function seems to be essential within the bacterial cell context. In addition, here we demonstrated that Mycobacterium tuberculosis dUTPase is fully functional in Mycobacterium smegmatis as it rescues the lethal knock-out phenotype. Our results indicate the potential of dUTPase as a target for antitubercular drugs and identify a genus-specific surface loop on the enzyme as a selective target. Public Library of Science 2012-05-24 /pmc/articles/PMC3360063/ /pubmed/22655049 http://dx.doi.org/10.1371/journal.pone.0037461 Text en Pecsi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Pecsi, Ildiko Hirmondo, Rita Brown, Amanda C. Lopata, Anna Parish, Tanya Vertessy, Beata G. Tóth, Judit The dUTPase Enzyme Is Essential in Mycobacterium smegmatis |
title | The dUTPase Enzyme Is Essential in Mycobacterium smegmatis
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title_full | The dUTPase Enzyme Is Essential in Mycobacterium smegmatis
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title_fullStr | The dUTPase Enzyme Is Essential in Mycobacterium smegmatis
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title_full_unstemmed | The dUTPase Enzyme Is Essential in Mycobacterium smegmatis
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title_short | The dUTPase Enzyme Is Essential in Mycobacterium smegmatis
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title_sort | dutpase enzyme is essential in mycobacterium smegmatis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360063/ https://www.ncbi.nlm.nih.gov/pubmed/22655049 http://dx.doi.org/10.1371/journal.pone.0037461 |
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