Dynamic biochemistry enzyme kinetics

This section mainly builds upon classic biochemistry to define the essential building blocks of metabolic networks and to describe their interactions in terms of enzyme-kinetic rate equations. Following the rationale described in the previous section, the construction of a model is the organization of the individual rate equations into a coherent whole the dynamic system that describes the time-dependent behavior of each metabolite. We proceed according to the scheme suggested by Wiechert and Takors [97], namely, (i) to define the elementary units of the system (Section III. A) (ii) to characterize the connectivity and interactions between the units, as given by the stoichiometry and regulatory interactions (Sections in.B and II1.C) and (iii) to express each interaction quantitatively by... 

The accurate prediction of enzyme kinetics from first principles is one of the central goals of theoretical biochemistry. Currently, there is considerable debate about the applicability of TST to compute rate constants of enzyme-catalyzed reactions. Classical TST is known to be insufficient in some cases, but corrections for dynamical recrossing and quantum mechanical tunneling can be included. Many effects go beyond the framework of TST, as those previously discussed, and the overall importance of these effects for the effective reaction rate is difficult (if not impossible) to determine experimentally. Efforts are presently oriented to compute the quasi-thermodynamic free energy of activation with chemical accuracy (i.e., 1 kcal mol-1), as a way to discern the importance of other effects from the comparison with the effective measured free energy of activation. 

Dose to Dose PBPK modeling permits reasonable extrapolation from one dose to another, if adequate information on physiology, physicochemical properties, and biochemistry is available. If the dynamic processes modeled by the PBPK approach are all directly proportional to administered concentrations, then the extrapolation can be relatively straightforward. However, this is not often the case, especially at higher doses, where saturation of metabolic or clearance processes can occur [14,19]. Further causes of nonlinearity of chemical kinetics include the induction and inhibition of metabolic enzymes [14], Despite these difficulties successful applications of dose extrapolation using PBPK models for many chemicals have been published [20,21], and... 

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