Symbolic control analysis of cellular systems

Akhurst, Timothy John (2011-03)

Thesis (PhD (Biochemistry))--University of Stellenbosch, 2011.

Thesis

ENGLISH ABSTRACT: Metabolic Control Analysis (MCA) provides a powerful quantitative framework for understanding and explaining the control and regulation within a cellular system. MCA allows the global control of a steady-state system to be quantified in terms of control coeficients, which we can express in terms of the local properties referred to as elasticity coeficients. MCA relates elasticities to control coeficients through a matrix inversion, thus allowing scientists to predict and quantify how the kinetics of the individual enzymes affect the systemic behaviour of cellular systems. Traditionally we solved this problem numerically, while we used algebraic and symbolic control analysis techniques less frequently. By using symbolic algebraic computation we present a general implementation of the symbolic matrix inversion of MCA, known as SymCA, which requires only the description of any allosteric modifier interactions and the stoichiometry of a cellular system. The algebraic expressions generated allow an in-depth analysis of the distribution of the control within a system and also of the parameters which exhibit the greatest effect on this control distribution. This also applies when the exact values for the elasticities or control coeficients are unknown. We have demonstrated that by quantifying the control patterns, referred to as `routes of regulation', inherent in all control coeficient expressions, we can gain insight into how perturbations are propagated through a cellular system and which regulatory pathways are favoured under changing conditions.

AFRIKAANSE OPSOMMING: Metaboliese Kontrole-Analise (MKA) bied 'n kragtige kwantitatiewe raamwerk om die beheer en regulering binne sellulere sisteme te verstaan en te verduidelik. 'n Sleutelaspek van MKA is dat die globale beheer van 'n sisteem met 'n bestendige toestand gekwantifiseer kan word in terme van kontrole-koefisente en dat hierdie koefisente uitgedruk kan word in terme van die sisteem se lokale eienskappe, genaamd elastisiteitskoefisente. Deur van matriksinversie gebruik te maak kan MKA die verband tussen elastisiteitskoefisente en kontrole-koefisente aflei wat mens in staat stel om te sien hoe die kinetika van die individuele ensiemreaksies die sisteemgedrag op sellulere vlak beinvloed. Die probleem word tradisioneel hoofsaaklik op numeriese wyse bereken terwyl die gebruik van algebraiese en simboliese kontrole-analise minder gereeld gebruik word. In hierdie proefskrif verskaf ons, deur van simboliese algebraiese metodes gebruik te maak, 'n generiese implementasie van die simboliese matriksinversie van MKA, genaamd SymCA, wat slegs 'n beskrywing van 'n sellulere sisteem se allosetriese interaksies en die stoichiometrie benodig. Die algebraiese uitdrukkings sodanig gegenereer stel mens in staat om 'n in-diepte analise te doen om vas te stel waar die beheer binne 'n sisteem le, asook watter parameters die grootste effek op die kontrole-verspreiding het. Dit geld selfs in die geval waar die presiese waardes van die elastisiteitskoefisente of kontrole-koefisente onbekend is. Hierdie proefskrif demonstreer hoe die kwantifisering van kontrole-patrone, ook gesien as 'roetes van regulering', wat inherent is aan kontrole-koefisent vergelykings, mens in staat stel om te sien hoe perturbasies in 'n sellulere sisteem voortplant en watter regulatoriese paaie bevoordeel word onder veranderde kondisies.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/6627

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