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Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6
Coq6 is an enzyme involved in the biosynthesis of coenzyme Q, a polyisoprenylated benzoquinone lipid essential to the function of the mitochondrial respiratory chain. In the yeast Saccharomyces cerevisiae, this putative flavin-dependent monooxygenase is proposed to hydroxylate the benzene ring of co...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726752/ https://www.ncbi.nlm.nih.gov/pubmed/26808124 http://dx.doi.org/10.1371/journal.pcbi.1004690 |
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author | Ismail, Alexandre Leroux, Vincent Smadja, Myriam Gonzalez, Lucie Lombard, Murielle Pierrel, Fabien Mellot-Draznieks, Caroline Fontecave, Marc |
author_facet | Ismail, Alexandre Leroux, Vincent Smadja, Myriam Gonzalez, Lucie Lombard, Murielle Pierrel, Fabien Mellot-Draznieks, Caroline Fontecave, Marc |
author_sort | Ismail, Alexandre |
collection | PubMed |
description | Coq6 is an enzyme involved in the biosynthesis of coenzyme Q, a polyisoprenylated benzoquinone lipid essential to the function of the mitochondrial respiratory chain. In the yeast Saccharomyces cerevisiae, this putative flavin-dependent monooxygenase is proposed to hydroxylate the benzene ring of coenzyme Q (ubiquinone) precursor at position C5. We show here through biochemical studies that Coq6 is a flavoprotein using FAD as a cofactor. Homology models of the Coq6-FAD complex are constructed and studied through molecular dynamics and substrate docking calculations of 3-hexaprenyl-4-hydroxyphenol (4-HP6), a bulky hydrophobic model substrate. We identify a putative access channel for Coq6 in a wild type model and propose in silico mutations positioned at its entrance capable of partially (G248R and L382E single mutations) or completely (a G248R-L382E double-mutation) blocking access to the channel for the substrate. Further in vivo assays support the computational predictions, thus explaining the decreased activities or inactivation of the mutated enzymes. This work provides the first detailed structural information of an important and highly conserved enzyme of ubiquinone biosynthesis. |
format | Online Article Text |
id | pubmed-4726752 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-47267522016-02-03 Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6 Ismail, Alexandre Leroux, Vincent Smadja, Myriam Gonzalez, Lucie Lombard, Murielle Pierrel, Fabien Mellot-Draznieks, Caroline Fontecave, Marc PLoS Comput Biol Research Article Coq6 is an enzyme involved in the biosynthesis of coenzyme Q, a polyisoprenylated benzoquinone lipid essential to the function of the mitochondrial respiratory chain. In the yeast Saccharomyces cerevisiae, this putative flavin-dependent monooxygenase is proposed to hydroxylate the benzene ring of coenzyme Q (ubiquinone) precursor at position C5. We show here through biochemical studies that Coq6 is a flavoprotein using FAD as a cofactor. Homology models of the Coq6-FAD complex are constructed and studied through molecular dynamics and substrate docking calculations of 3-hexaprenyl-4-hydroxyphenol (4-HP6), a bulky hydrophobic model substrate. We identify a putative access channel for Coq6 in a wild type model and propose in silico mutations positioned at its entrance capable of partially (G248R and L382E single mutations) or completely (a G248R-L382E double-mutation) blocking access to the channel for the substrate. Further in vivo assays support the computational predictions, thus explaining the decreased activities or inactivation of the mutated enzymes. This work provides the first detailed structural information of an important and highly conserved enzyme of ubiquinone biosynthesis. Public Library of Science 2016-01-25 /pmc/articles/PMC4726752/ /pubmed/26808124 http://dx.doi.org/10.1371/journal.pcbi.1004690 Text en © 2016 Ismail 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 Ismail, Alexandre Leroux, Vincent Smadja, Myriam Gonzalez, Lucie Lombard, Murielle Pierrel, Fabien Mellot-Draznieks, Caroline Fontecave, Marc Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6 |
title | Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6 |
title_full | Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6 |
title_fullStr | Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6 |
title_full_unstemmed | Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6 |
title_short | Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6 |
title_sort | coenzyme q biosynthesis: evidence for a substrate access channel in the fad-dependent monooxygenase coq6 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726752/ https://www.ncbi.nlm.nih.gov/pubmed/26808124 http://dx.doi.org/10.1371/journal.pcbi.1004690 |
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