Thesis (MSc)--Stellenbosch University, 2013. / 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. / National Research Foundation
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/80280 |
| Date | 25 February 2013 |
| Creators | Van Zyl, Jalene |
| Contributors | Hofmeyr, J.- H. S., Rohwer, J. M., Stellenbosch University. Faculty of Science. Dept. of Biochemistry. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | xii, 111 p. : ill. |
| Rights | Stellenbosch University |
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