Systems approaches to modelling pathways and networks.

Peer reviewedPreprin

Analytical review of passive mass transfer of water vapor in a space suit

Engineering study and analysis of water vapor mass transfer in space sui

The Carbon Assimilation Network in Escherichia coli Is Densely Connected and Largely Sign-Determined by Directions of Metabolic Fluxes

Gene regulatory networks consist of direct interactions but also include indirect interactions mediated by metabolites and signaling molecules. We describe how these indirect interactions can be derived from a model of the underlying biochemical reaction network, using weak time-scale assumptions in combination with sensitivity criteria from metabolic control analysis. We apply this approach to a model of the carbon assimilation network in Escherichia coli. Our results show that the derived gene regulatory network is densely connected, contrary to what is usually assumed. Moreover, the network is largely sign-determined, meaning that the signs of the indirect interactions are fixed by the flux directions of biochemical reactions, independently of specific parameter values and rate laws. An inversion of the fluxes following a change in growth conditions may affect the signs of the indirect interactions though. This leads to a feedback structure that is at the same time robust to changes in the kinetic properties of enzymes and that has the flexibility to accommodate radical changes in the environment

Hybrid dynamic/static method for large-scale simulation of metabolism

BACKGROUND: Many computer studies have employed either dynamic simulation or metabolic flux analysis (MFA) to predict the behaviour of biochemical pathways. Dynamic simulation determines the time evolution of pathway properties in response to environmental changes, whereas MFA provides only a snapshot of pathway properties within a particular set of environmental conditions. However, owing to the large amount of kinetic data required for dynamic simulation, MFA, which requires less information, has been used to manipulate large-scale pathways to determine metabolic outcomes. RESULTS: Here we describe a simulation method based on cooperation between kinetics-based dynamic models and MFA-based static models. This hybrid method enables quasi-dynamic simulations of large-scale metabolic pathways, while drastically reducing the number of kinetics assays needed for dynamic simulations. The dynamic behaviour of metabolic pathways predicted by our method is almost identical to that determined by dynamic kinetic simulation. CONCLUSION: The discrepancies between the dynamic and the hybrid models were sufficiently small to prove that an MFA-based static module is capable of performing dynamic simulations as accurately as kinetic models. Our hybrid method reduces the number of biochemical experiments required for dynamic models of large-scale metabolic pathways by replacing suitable enzyme reactions with a static module

Control of hepatic fatty acid oxidation in suckling rats

In this thesis, I use metabolic control analysis to investigate quantitatively, the control of neonatal hepatic fatty acid oxidation and ketogenesis. Specifically, I model, report and discuss the control of hepatic fatty acid oxidation, Krebs cycle and ketogenic fluxes by mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I), in hepatocytes or mitochondria isolated from suckling rats, under physiological and (patho)physiological conditions, mimicking healthy and diseased states. My work has: (a) provided the first quantitative assessment of the control exerted by CPT I over carbon fluxes from palmitate, octanoate and palmitate: octanoate mixtures, in hepatocytes isolated from suckling rats; (b) provided a quantitative assessment of the control exerted by CPT I over ketogenesis and total carbon flux from palmitate, in a re-defined system, in mitochondria isolated from suckling or adult rats (Krauss, et al., 1996); (c) shown that the numerical value of the flux control coefficient for CPT I over ketogenesis changes with developmental stage and is lower in suckling rats than in adult rats in both hepatocyte and mitochondrial systems; (d) demonstrated that the numerical value of the flux control coefficient for CPT I over ketogenesis changes in response to different substrates; (e) indicated that whilst in adult rats, CPT I exerts a high level of control over ketogenesis in neonatal rats, CPT I is not 'rate-limiting' over ketogenesis, under physiological conditions; (f) provided the first quantitative assessment of the control exerted by CPT I over carbon fluxes from palmitate in an in vitro model of neonatal sepsis; (g) demonstrated that the potential of CPT I to control ketogenesis increases under certain (patho)physiological conditions; (h) provided an investigation into hepatocyte respiration under (patho)physiological conditions and has shown that in this in vitro model of neonatal sepsis, oxygen consumption is increased