Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 288, Issue 3, Pages E633-E644Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00239.2004
Keywords
network thermodynamics; nonequilibrium steady state; biochemical network
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Funding
- NIGMS NIH HHS [GM-068610] Funding Source: Medline
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Thermodynamic-based constraints on biochemical fluxes and concentrations are applied in concert with mass balance of fluxes in glycogenesis and glycogenolysis in a model of hepatic cell metabolism. Constraint-based modeling methods that facilitate predictions of reactant concentrations, reaction potentials, and enzyme activities are introduced to identify putative regulatory and control sites in biological networks by computing the minimal control scheme necessary to switch between metabolic modes. Computational predictions of control sites in glycogenic and glycogenolytic operational modes in the hepatocyte network compare favorably with known regulatory mechanisms. The developed hepatic metabolic model is used to computationally analyze the impairment of glucose production in von Gierke's and Hers' diseases, two metabolic diseases impacting glycogen metabolism. The computational methodology introduced here can be generalized to identify downstream targets of agonists, to systematically probe possible drug targets, and to predict the effects of specific inhibitors ( or activators) on integrated network function.
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