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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.

Otero JM, Papadakis MA, Udatha DB, Nielsen J, Panagiotou G - PLoS ONE (2010)

Bottom Line: Identifying causative biological networks associated with relevant phenotypes is essential in the field of systems biology.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Center for Microbial Biotechnology, Technical University of Denmark, Lyngby, Denmark.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions: 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.

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Related in: MedlinePlus

Homology modeling of the human brain protein BRP44 and ligand binding site prediction.(A) Molecular surface structure of BRP44 showing predicted binding site-1 in cyan. (B) Ramachandran plot of BRP44 structure obtained from Procheck program. None of the amino acid residues are in disallowed regions.
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pone-0013606-g004: Homology modeling of the human brain protein BRP44 and ligand binding site prediction.(A) Molecular surface structure of BRP44 showing predicted binding site-1 in cyan. (B) Ramachandran plot of BRP44 structure obtained from Procheck program. None of the amino acid residues are in disallowed regions.

Mentions: Two potential protein-ligand binding sites from a total of 10 predicted sites (using Q-SiteFinder) were selected for molecular docking studies. Predicted site-1 contained 13 amino acids surrounding the cavity and had a site volume of 201 Å3. Predicted site-2 contained 10 amino acids surrounding the cavity and had a site volume of 115 Å3. Molecular docking was performed against the BRP44 predicted binding site residues using FA as the ligand. Analysis of best ligand pose energies indicated that predicted site-1 had higher affinity for FA. The molecular surface structure of BRP44 with predicted binding site-1 is shown in Figure 4A along with the Ramachandran plot obtained from Procheck (Figure 4B).


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

Otero JM, Papadakis MA, Udatha DB, Nielsen J, Panagiotou G - PLoS ONE (2010)

Homology modeling of the human brain protein BRP44 and ligand binding site prediction.(A) Molecular surface structure of BRP44 showing predicted binding site-1 in cyan. (B) Ramachandran plot of BRP44 structure obtained from Procheck program. None of the amino acid residues are in disallowed regions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963615&req=5

pone-0013606-g004: Homology modeling of the human brain protein BRP44 and ligand binding site prediction.(A) Molecular surface structure of BRP44 showing predicted binding site-1 in cyan. (B) Ramachandran plot of BRP44 structure obtained from Procheck program. None of the amino acid residues are in disallowed regions.
Mentions: Two potential protein-ligand binding sites from a total of 10 predicted sites (using Q-SiteFinder) were selected for molecular docking studies. Predicted site-1 contained 13 amino acids surrounding the cavity and had a site volume of 201 Å3. Predicted site-2 contained 10 amino acids surrounding the cavity and had a site volume of 115 Å3. Molecular docking was performed against the BRP44 predicted binding site residues using FA as the ligand. Analysis of best ligand pose energies indicated that predicted site-1 had higher affinity for FA. The molecular surface structure of BRP44 with predicted binding site-1 is shown in Figure 4A along with the Ramachandran plot obtained from Procheck (Figure 4B).

Bottom Line: Identifying causative biological networks associated with relevant phenotypes is essential in the field of systems biology.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Center for Microbial Biotechnology, Technical University of Denmark, Lyngby, Denmark.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus