Section: New Results

Inferring metabolic models

Participants : David James Sherman [correspondant] , Pascal Durrens, Tiphaine Martin, Nicolás Loira, Anna Zhukova.

In collaboration with Prof Jean-Marc Nicaud's lab at the INRA Grignon, we developed the first functional genome-scale metabolic model of an oleaginous yeast. Most work in producing genome-scale metabolic models has focused on model organisms, in part due to the cost of obtaining well-annotated genome sequences and sufficiently complete experimental data for refining and verifying the models. However, for many fungal genomes of biotechnological interest, the combination of large-scale sequencing projects and in-depth experimental studies has made it feasible to undertake metabolic network reconstruction for a wider range of organisms.

An excellent representative of this new class of organisms is Yarrowia lipolytica, an oleaginous yeast studied experimentally for its role as a food contaminant and its use in bioremediation and cell factory applications. As one of the hemiascomycetous yeasts completely sequenced in the Génolevures program it enjoys a high quality manual annotation by a network of experts. It is also an ideal subject for studying the role of species-specific expansion of paralogous families, a considerable challenge for eukaryotes in genome-scale metabolic construction. To these ends, we undertook a complete reconstruction of the Y. lipolytica metabolic network.

Methods: A draft model was extrapolated from the S. cerevisiae model iIN800, using in silico methods including enzyme conservation predicted using Génolevures and reaction mapping maintaining compartments. This draft was curated by a group of experts in Y. lipolytica metabolism, and iteratively improved and validated through comparison with experimental data by flux balance analysis. Gap filling, species-specific reactions, and the addition of compartments with the corresponding transport reactions were among the improvements that most affected accuracy.

Results: We produced an accurate functional model for Y. lipolytica, MODEL1111190000 in Biomodels.net , that has been qualitatively validated against gene knockouts.