Evaluation of predicted network modules in yeast metabolism using NMR-based metabolite profiling.
Genome-scale metabolic models promise important insights into cell function. However, the definition of pathways and functional network modules within these models, and in the biochemical literature in general, is often based on intuitive reasoning. Although mathematical methods have been proposed to identify modules, which are defined as groups of reactions with correlated fluxes, there is a need for experimental verification. We show here that multivariate statistical analysis of the NMR-derived intra- and extracellular metabolite profiles of single-gene deletion mutants in specific metabolic pathways in the yeast Saccharomyces cerevisiae identified outliers whose profiles were markedly different from those of the other mutants in their respective pathways. Application of flux coupling analysis to a metabolic model of this yeast showed that the deleted gene in an outlying mutant encoded an enzyme that was not part of the same functional network module as the other enzymes in the pathway. We suggest that metabolomic methods such as this, which do not require any knowledge of how a gene deletion might perturb the metabolic network, provide an empirical method for validating and ultimately refining the predicted network structure.
Bundy
Jacob G
JG
Department of Biochemistry, University of Cambridge, Cambridge, UK.
Papp
Balázs
B
Harmston
Rebecca
R
Browne
Roy A
RA
Clayson
Edward M
EM
Burton
Nicola
N
Reece
Richard J
RJ
Oliver
Stephen G
SG
Brindle
Kevin M
KM
D005800:Genes, Fungal; D016681:Genome, Fungal; D006019:Glycolysis; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D009154:Mutation; D011392:Proline / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014199:Trehalose / Q000096:biosynthesis / Q000378:metabolism
D011743:Pyrimidines; D029701:Saccharomyces cerevisiae Proteins; D011392:Proline; D014199:Trehalose; C030986:pyrimidine