Further developments towards a genome-scale metabolic model of yeast

Abstract

Background: To date, several genome-scale network reconstructions have been used to describe the metabolism of the yeast Saccharomyces cerevisiae, each differing in scope and content. The recent community-driven reconstruction, while rigorously evidenced and well annotated, under-represented metabolite transport, lipid metabolism and other pathways, and was not amenable to constraint-based analyses because of lack of pathway connectivity.

Results: We have expanded the yeast network reconstruction to incorporate many new reactions from the literature and represented these in a well-annotated and standards-compliant manner. The new reconstruction comprises 1102 unique metabolic reactions involving 924 unique metabolites--significantly larger in scope than any previous reconstruction. The representation of lipid metabolism in particular has improved, with 234 out of 268 enzymes linked to lipid metabolism now present in at least one reaction. Connectivity is emphatically improved, with more than 90% of metabolites now reachable from the growth medium constituents. The present updates allow constraint-based analyses to be performed; viability predictions of single knockouts are comparable to results from in vivo experiments and to those of previous reconstructions.

Conclusions: We report the development of the most complete reconstruction of yeast metabolism to date that is based upon reliable literature evidence and richly annotated according to MIRIAM standards. The reconstruction is available in the Systems Biology Markup Language (SBML) and via a publicly accessible database http://www.comp-sys-bio.org/yeastnet/.

Figure 1

SBML example. Simplified example of MIRIAM-compliant SBML, whereby an enzyme is annotated with reference to the databases UniProt, SGD and PubMed, respectively.

Figure 2

Comparison of reconstructions in terms of enzymes present. The reconstruction presented here contains 124 more enzymes than Yeast 1.0, 61 of which have not been considered by any of the other reconstructions. Yeast 1.0 was also improved upon through better curation leading to the removal of (2 + 9 + 21 =) 32 enzymes. A further (6 + 13 + 18 =) 37 enzymes from iMM908 and iIM800 were not added to the reconstruction.

Figure 3

Comparison of the coverage of lipid metabolism enzymes by the different reconstructions. At least one reaction in a reconstruction is catalyzed by each enzyme. On top of extending Yeast 1.0 by (1 + 9 + 46 =) 56 enzymes from iMM904 and iIN800, a further 49 enzymes uniquely appear in this latest reconstruction. Three reactions common to iMM904 and iIN800, plus 31 others, have not been incorporated for lack of evidence.

Figure 4

Visualisation of connectivity analysis. Metabolites that are unreachable (in red) were identified with a graphical analysis, by locating metabolites that are disconnected from the extracellular medium. Flux variability analysis identified reactions that must have zero flux (in blue) because they lead to dead-end metabolites.