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Title: A study of coenzyme A metabolism and function in mammalian cells
Author: Monteil, P. Y.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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CoA is well established as a metabolic cofactor in numerous oxidative and biosynthetic pathways. The levels of CoA usually remain within a tight range, however these have been shown to change in response to nutritional state, fibrate drugs and several pathological conditions. Although the mechanisms that alter CoA levels are not fully understood, the fluctuations in CoA can influence the cellular processes it regulates. The regulatory roles of CoA have mainly been studied in the context of feedback/ feed forward regulation of metabolic pathways or enzymes, yet very little is known about its role as a regulator of cellular function. In addition to its action as a cofactor, a few reports have indicated that CoA binds to and regulates proteins through allosteric and covalent modification, suggesting wider regulatory roles for CoA. The aim of this thesis was therefore to gain a greater understanding of the function of CoA as a regulator of cellular processes. Initially, conditions for extracting and measuring CoA levels in cultured cells were developed and optimised. CoA levels were much lower in cultured HepG2 cells compared to liver and did not respond in the same way when treated with extracellular stimuli. A 2-fold increase in CoA levels, through over-expression of the enzyme PanK1β, did result in the novel finding that CoA has a negative effect on cell growth. This was accompanied by increased acetylation of a large number of proteins and also an increase in lactate production. In addition, affinity purification with CoA Sepharose, followed by mass spectrometry, pulled down several proteins, previously unknown to bind to CoA, which regulate a wide range of cellular processes. Together, the data from this thesis has provided a greater insight into the wider role of CoA as a regulator of cellular function.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available