Abstract
A new formalism to describe metabolic fluxes as well as membrane transport processes was developed. The new flux equations are comparable to other phenomenological laws. Michaelis-Menten like expressions, as well as flux equations of nonequilibrium thermodynamics, can be regarded as special cases of these new equations. For metabolic network modeling, variable conductances and driving forces are required to enable pathway control and to allow a rapid response to perturbations. When applied to oxidative phosphorylation, results of simulations show that whole oxidative phosphorylation cannot be described as a two-flux-system according to nonequilibrium thermodynamics, although all coupled reactions per se fulfill the equations of this theory. Simulations show that activation of ATP-coupled load reactions plus glucose oxidation is brought about by an increase of only two different conductances: a [Ca2+] dependent increase of cytosolic load conductances, and an increase of phosphofructokinase conductance by [AMP], which in turn becomes increased through [ADP] generation by those load reactions. In ventricular myocytes, this feedback mechanism is sufficient to increase cellular power output and O2 consumption several fold, without any appreciable impairment of energetic parameters. Glucose oxidation proceeds near maximal power output, since transformed input and output conductances are nearly equal, yielding an efficiency of about 0.5. This conductance matching is fulfilled also by glucose oxidation of β-cells. But, as a price for the metabolic mechanism of glucose recognition, β-cells have only a limited capability to increase their power output.
Highlights
In recent years mathematical modeling of metabolic pathways became increasingly important as a helpful tool for a deeper understanding of biochemical reaction networks in cellular metabolism and energetics
In previous articles (Diederichs, [6,10]) a new phenomenological type of flux equation to describe membrane transport reactions and enzyme-catalyzed reactions as they occur in the living cell, was introduced
The new formalism combines some characteristics known from enzyme-catalyzed reactions with energetic relations of nonequilibrium thermodynamics (NET)
Summary
In recent years mathematical modeling of metabolic pathways became increasingly important as a helpful tool for a deeper understanding of biochemical reaction networks in cellular metabolism and energetics. In two recently published articles [6,10], a new flux equation was introduced, which allows both, the description of kinetic flux behavior similar to Michaelis-Menten type equations [11], as well as the treatment of energetic relations known from methods of nonequilibrium thermodynamics (NET)[12,13,14,15]. The dissipation function is suited for the treatment of energetic relations of metabolic pathways like glucose oxidation. In this context, it seemed essential to test the applicability of flux equations to widely accepted results from
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