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Open Access Highly Accessed Research article

Redox balance is key to explaining full vs. partial switching to low-yield metabolism

Milan JA van Hoek123 and Roeland MH Merks1234*

Author Affiliations

1 Centrum Wiskunde & Informatica, Life Sciences, Science Park 123, 1098 XG Amsterdam, The Netherlands

2 Netherlands Institute for Systems Biology, Science Park 123, 1098 XG Amsterdam, The Netherlands

3 Netherlands Consortium for Systems Biology, Amsterdam, The Netherlands

4 Mathematical Institute, Leiden University, P.O. Box 9512, 2300 RA Leiden, The Netherlands

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BMC Systems Biology 2012, 6:22  doi:10.1186/1752-0509-6-22

Published: 24 March 2012

Abstract

Background

Low-yield metabolism is a puzzling phenomenon in many unicellular and multicellular organisms. In abundance of glucose, many cells use a highly wasteful fermentation pathway despite the availability of a high-yield pathway, producing many ATP molecules per glucose, e.g., oxidative phosphorylation. Some of these organisms, including the lactic acid bacterium Lactococcus lactis, downregulate their high-yield pathway in favor of the low-yield pathway. Other organisms, including Escherichia coli do not reduce the flux through the high-yield pathway, employing the low-yield pathway in parallel with a fully active high-yield pathway. For what reasons do some species use the high-yield and low-yield pathways concurrently and what makes others downregulate the high-yield pathway? A classic rationale for metabolic fermentation is overflow metabolism. Because the throughput of metabolic pathways is limited, influx of glucose exceeding the pathway's throughput capacity is thought to be redirected into an alternative, low-yield pathway. This overflow metabolism rationale suggests that cells would only use fermentation once the high-yield pathway runs at maximum rate, but it cannot explain why cells would decrease the flux through the high-yield pathway.

Results

Using flux balance analysis with molecular crowding (FBAwMC), a recent extension to flux balance analysis (FBA) that assumes that the total flux through the metabolic network is limited, we investigate the differences between Saccharomyces cerevisiae and L. lactis that downregulate the high-yield pathway at increasing glucose concentrations, and E. coli, which keeps the high-yield pathway functioning at maximal rate. FBAwMC correctly predicts the metabolic switching mode in these three organisms, suggesting that metabolic network architecture is responsible for differences in metabolic switching mode. Based on our analysis, we expect gradual, "overflow-like" switching behavior in organisms that have an additional energy-yielding pathway that does not consume NADH (e.g., acetate production in E. coli). Flux decrease through the high-yield pathway is expected in organisms in which the high-yield and low-yield pathways compete for NADH. In support of this analysis, a simplified model of metabolic switching suggests that the extra energy generated during acetate production produces an additional optimal growth mode that smoothens the metabolic switch in E. coli.

Conclusions

Maintaining redox balance is key to explaining why some microbes decrease the flux through the high-yield pathway, while other microbes use "overflow-like" low-yield metabolism.

Keywords:
Metabolic switching; Genome-scale metabolic model; Flux Balance Analysis with Molecular Crowding; Overflow metabolism; Redox balance; Escherichia coli; Lactococcus lactis; Saccharomyces cerevisiae