Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.

<h4>Background</h4>Identifying causative biological networks associated with relevant phenotypes is essential in the field of systems biology. We used ferulic acid (FA) as a model antioxidant to characterize the global expression programs triggered by this small molecule and decipher the...

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Autores principales:	Jose M Otero, Manos A Papadakis, D B R K Gupta Udatha, Jens Nielsen, Gianni Panagiotou
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b87bd3b422604ccdb51674eaadecff68
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spelling	oai:doaj.org-article:b87bd3b422604ccdb51674eaadecff682021-11-18T07:02:55ZYeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.1932-620310.1371/journal.pone.0013606https://doaj.org/article/b87bd3b422604ccdb51674eaadecff682010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21049050/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Identifying causative biological networks associated with relevant phenotypes is essential in the field of systems biology. We used ferulic acid (FA) as a model antioxidant to characterize the global expression programs triggered by this small molecule and decipher the transcriptional network controlling the phenotypic adaptation of the yeast Saccharomyces cerevisiae.<h4>Methodology/principal findings</h4>By employing a strict cut off value during gene expression data analysis, 106 genes were found to be involved in the cell response to FA, independent of aerobic or anaerobic conditions. Network analysis of the system guided us to a key target node, the FMP43 protein, that when deleted resulted in marked acceleration of cellular growth (∼15% in both minimal and rich media). To extend our findings to human cells and identify proteins that could serve as drug targets, we replaced the yeast FMP43 protein with its human ortholog BRP44 in the genetic background of the yeast strain Δfmp43. The conservation of the two proteins was phenotypically evident, with BRP44 restoring the normal specific growth rate of the wild type. We also applied homology modeling to predict the 3D structure of the FMP43 and BRP44 proteins. The binding sites in the homology models of FMP43 and BRP44 were computationally predicted, and further docking studies were performed using FA as the ligand. The docking studies demonstrated the affinity of FA towards both FMP43 and BRP44.<h4>Conclusions</h4>This study proposes a hypothesis on the mechanisms yeast employs to respond to antioxidant molecules, while demonstrating how phenome and metabolome yeast data can serve as biomarkers for nutraceutical discovery and development. Additionally, we provide evidence for a putative therapeutic target, revealed by replacing the FMP43 protein with its human ortholog BRP44, a brain protein, and functionally characterizing the relevant mutant strain.Jose M OteroManos A PapadakisD B R K Gupta UdathaJens NielsenGianni PanagiotouPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13606 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jose M Otero Manos A Papadakis D B R K Gupta Udatha Jens Nielsen Gianni Panagiotou Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.
description	<h4>Background</h4>Identifying causative biological networks associated with relevant phenotypes is essential in the field of systems biology. We used ferulic acid (FA) as a model antioxidant to characterize the global expression programs triggered by this small molecule and decipher the transcriptional network controlling the phenotypic adaptation of the yeast Saccharomyces cerevisiae.<h4>Methodology/principal findings</h4>By employing a strict cut off value during gene expression data analysis, 106 genes were found to be involved in the cell response to FA, independent of aerobic or anaerobic conditions. Network analysis of the system guided us to a key target node, the FMP43 protein, that when deleted resulted in marked acceleration of cellular growth (∼15% in both minimal and rich media). To extend our findings to human cells and identify proteins that could serve as drug targets, we replaced the yeast FMP43 protein with its human ortholog BRP44 in the genetic background of the yeast strain Δfmp43. The conservation of the two proteins was phenotypically evident, with BRP44 restoring the normal specific growth rate of the wild type. We also applied homology modeling to predict the 3D structure of the FMP43 and BRP44 proteins. The binding sites in the homology models of FMP43 and BRP44 were computationally predicted, and further docking studies were performed using FA as the ligand. The docking studies demonstrated the affinity of FA towards both FMP43 and BRP44.<h4>Conclusions</h4>This study proposes a hypothesis on the mechanisms yeast employs to respond to antioxidant molecules, while demonstrating how phenome and metabolome yeast data can serve as biomarkers for nutraceutical discovery and development. Additionally, we provide evidence for a putative therapeutic target, revealed by replacing the FMP43 protein with its human ortholog BRP44, a brain protein, and functionally characterizing the relevant mutant strain.
format	article
author	Jose M Otero Manos A Papadakis D B R K Gupta Udatha Jens Nielsen Gianni Panagiotou
author_facet	Jose M Otero Manos A Papadakis D B R K Gupta Udatha Jens Nielsen Gianni Panagiotou
author_sort	Jose M Otero
title	Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.
title_short	Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.
title_full	Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.
title_fullStr	Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.
title_full_unstemmed	Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.
title_sort	yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/b87bd3b422604ccdb51674eaadecff68
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Yeast biological networks unfold the interplay of antioxidants, genome and phenotype, and reveal a novel regulator of the oxidative stress response.

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