Yeast Biological Networks Unfold the Interplay of Antioxidants, Genome and Phenotype, and Reveal a Novel Regulator of the Oxidative Stress Response
Journal article, 2010

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.

Author

José Manuel Otero

Technical University of Denmark (DTU)

Chalmers, Chemical and Biological Engineering, Industrial biotechnology

M.A. Papadakis

Technical University of Denmark (DTU)

Gupta Udatha

Chalmers, Chemical and Biological Engineering, Industrial biotechnology

Jens B Nielsen

Chalmers, Chemical and Biological Engineering, Life Sciences, System Biology

Gianni Panagiotou

Technical University of Denmark (DTU)

PLoS ONE

1932-6203 (ISSN)

Vol. 5 10 e13606- e13606

Areas of Advance

Life Science Engineering (2010-2018)

Subject Categories

Microbiology in the medical area

Bioinformatics and Systems Biology

Other Industrial Biotechnology

DOI

10.1371/journal.pone.0013606

More information

Latest update

7/22/2019