title: From metabolomics to fluxomics: a computational procedure to translate metabolite profiles into metabolic fluxes.
abstract: We describe a believed-novel procedure for translating metabolite profiles (metabolome) into the set of metabolic fluxes (fluxome) from which they originated. Methodologically, computational modeling is integrated with an analytical platform comprising linear optimization, continuation and dynamic analyses, and metabolic control. The procedure was tested with metabolite profiles obtained from ex vivo mice Langendorff-heart preparations perfused with glucose. The metabolic profiles were analyzed using a detailed kinetic model of the glucose catabolic pathways including glycolysis, pentose phosphate (PP), glycogenolysis, and polyols to translate the glucose metabolome of the heart into the fluxome. After optimization, the ability of the model to simulate the initial metabolite profile was confirmed, and metabolic fluxes as well as the structure of control and regulation of the glucose catabolic network could be calculated. We show that the step catalyzed by phosphofructokinase together with ATP demand and glycogenolysis exert the highest control on the glycolytic flux. The negative flux control exerted by phosphofructokinase on the PP and polyol pathways revealed that the extent of glycolytic flux directly affects flux redirection through these pathways, i.e., the higher the glycolytic flux the lower the PP and polyols. This believed-novel methodological approach represents a step forward that may help in designing therapeutic strategies targeted to diagnose, prevent, and treat metabolic diseases.
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Cortassa
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Viviane
authors.initials: V
authors.lastname: Caceres
authors.affiliation: Metabolon, Inc., Durham, North Carolina.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bell
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: maon1@jhmi.edu.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Aon
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D005947:Glucose / Q000378:metabolism*; D050261:Glycogenolysis; D006019:Glycolysis; D007700:Kinetics; D016014:Linear Models; D055442:Metabolome / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010427:Pentose Phosphate Pathway; D011108:Polymers / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D011108:Polymers; C024617:polyol; D009243:NAD; D009249:NADP; D000251:Adenosine Triphosphatases; D005947:Glucose