The quantification of metabolic regulation

Van Zyl, Jalene (2013-02-25)

Thesis (MSc)--Stellenbosch University, 2013.

Thesis

ENGLISH ABSTRACT: Metabolic systems are open systems continually subject to changes in the surrounding environment that cause uctuations in the state variables and perturbations in the system parameters. However, metabolic systems have mechanisms to keep them dynamically and structurally stable in the face of these changes. In addition, metabolic systems also cope with large changes in the uxes through the pathways, not letting metabolite concentrations vary wildly. Quantitative measures have previously been proposed for "metabolic regulation", using the quantitative framework of Metabolic Control Analysis. However, the term "regulation" is so loosely used so that its content is mostly lost. These di erent measures of regulation have also not been applied to a model and comparably investigated prior to this study. Hence, this study analyses the usefulness of the di erent quantitative measures in answering di erent types of regulatory questions. Thus, the aim of this study was to distinguish the above mentioned aspects of metabolic regulation and to nd appropriate quantitative measures for each, namely dynamic stability, structurally stability, and homeostasis. Dynamic stability is the property of a steady state to return to its original state after a perturbation in a metabolite in the system, and can be analysed in terms of self and internal-response coe cients. Structural stability is concerned with the change in steady state after a perturbation of a parameter in the system, and can be analysed in terms of concentration-response coe cients. Furthermore, it is shown that control patterns are useful in understanding which system properties determine structural stability and to what degree. Homeostasis is de ned as the change in the steady-state concentration of a metabolite relative to the change in the steady-state ux through the metabolite pool following a perturbation in a system parameter, and co-response coe cients are proposed as quantitative measures of homeostasis. More speci cally, metabolite-ux coresponse coe cients allow the de nition of an index that quanti es to which degree a metabolite is homeostatically regulated. A computational model of a simple linear metabolic sequence subject to feedback inhibition with di erent sets of parameters provided a test-bed for the quantitative analysis of metabolic regulation. Log-log rate characteristics and parameter portraits of steady-state variables, as well as response and elasticity coe cients were used to analyse the steady-state behaviour and control properties of the system. This study demonstrates the usefulness of generic models based on proper enzyme kinetics to further our understanding of metabolic behaviour, control and regulation and has laid the groundwork for future studies of metabolic regulation of more complex core models or of models of real systems.

AFRIKAANSE OPSOMMING: Metaboliese sisteme is oop sisteme wat gedurig blootgestel word aan `n uktuerende omgewing. Hierdie uktuasies lei tot veranderinge in beide interne veranderlikes en parameters van metaboliese sisteme. Metaboliese sisteme besit egter meganismes om dinamies en struktureel stabiel te bly. Verder verseker hierdie meganismes ook dat die konsentrasies van interne metaboliete relatief konstant bly ten spyte van groot veranderinge in uksie deur die metaboliese pad waarvan hierdie metaboliete deel vorm. Kwantitatiewe maatstawwe is voorheen voorgestel vir "metaboliese regulering", gebaseer op die raamwerk van Metaboliese Kontrole Analise. Die onkritiese gebruik van die term "regulering" ontneem egter hierdie konsep van sinvolle betekenis. Voor hierdie studie is die voorgestelde maatstawwe van regulering nog nie toegepas op 'n model ten einde hulle met mekaar te vergelyk nie. Die huidige studie ondersoek die toepaslikheid van die verskillende maatstawwe om verskillende tipe vrae oor regulering te beantwoord. Die doelwit van hierdie studie was om aspekte van metaboliese regulering, naamlik dinamiese stabiliteit, strukturele stabiliteit en homeostase, te onderskei, asook om 'n gepaste maatstaf vir elk van die verskillende aspekte te vind. Dinamiese stabiliteit is 'n eienskap van 'n bestendige toestand om terug te keer na die oorspronklike toestand na perturbasie van die konsentrasie van 'n interne metaboliet. Hierdie aspek van regulering kan in terme van interne respons en self-respons koeffi siente geanaliseer word. Strukturele stabiliteit van 'n bestendige toestand beskryf die mate van verandering van die bestendige toestand nadat 'n parameter van die sisteem geperturbeer is, en kan in terme van konsentrasie-responskoeffisiente geanaliseer word. Verder wys hierdie studie dat kontrole patrone van nut is om vas te stel watter eienskappe van 'n sisteem die strukturele stabiliteit bepaal en tot watter mate. Homeostase word gede finieer as die verandering in die konsentrasie van 'n interne metaboliet relatief tot die verandering in die uksie deur daardie metaboliese poel nadat 'n parameter van die sisteem verander het. Vir die analise van hierdie aspek van regulering word ko-responskoe ffisiente as 'n maatstaf voorgestel. Meer spesi ek kan metaboliet- uksie ko-responskoeff siente gebruik word om `n indeks te de nieer wat meet tot watter mate 'n metaboliet homeostaties gereguleer word. 'n Rekenaarmatige model van 'n eenvoudige lineere metaboliese sekwens wat onderhewig is aan terugvoer inhibisie is gebruik om die verskillende aspekte van metaboliese regulering kwantitatief te analiseer met vier verskillende stelle parameters. Dubbel-logaritmiese snelheidskenmerke en parameter portrette van bestendige toestandsveranderlikes, asook van respons- en elastisiteit koeffisente is gebruik om die bestendige toestandsgedrag en kontrole eienskappe van die sisteem te analiseer. Hierdie studie demonstreer die nut van generiese modelle wat op korrekte ensiemkinetika gebaseer is om ons verstaan van metaboliese gedrag, kontrole en regulering te verdiep. Verder dien hierdie studie as grondslag vir toekomstige studies van metaboliese regulering van meer ingewikkelde kernmodelle of modelle van werklike sisteme.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/80280
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