Investigating the regulation and cellular functions of CoA
Doctoral thesis, UCL (University College London).
Coenzyme A is a biologically vital molecule which partakes in a multitude of biosynthetic and metabolic processes involving carbohydrates, amino acids and lipids. The pathway for biosynthesising Coenzyme A has been conserved in bacteria, yeast, plants and man. Loss of function of the first enzyme in that pathway is implicated in a severe human neurological disorder. Coenzyme A Synthase (CoASy) is a rate-limiting, bifunctional enzyme which catalyses the last two steps in that pathway. Very little is known about how it is regulated or what other proteins it associates with. Previous studies have indicated that CoASy interacts with kinases involved in the regulation of cell growth signalling pathways, such as ribosomal S6 Kinase and Phosphoinositide 3-Kinase. Fly and plant models suggest that disrupted CoASy activity can have a negative impact on growth, DNA integrity and lipid synthesis. There are currently no animal models for CoASy dysfunction. The first part of this thesis details the creation of targeting constructs for generating murine embryonic stem (ES) cells with a loss-of-function mutation in one of the catalytic domains in CoASy. These ES cells could then be used to create knock-in mutant mice deficient in the ability to synthesise Coenzyme A. The second part of the thesis covers the investigation into novel CoASy binding partners, in order to elucidate how CoASy might be regulated and what other pathways this protein might be involved in. The proteins identified have very different primary functions to one another, but do share roles in promoting cell survival and regulating apoptosis. Cells overexpressing CoA Synthase appear to be resistant to the induction of apoptosis. CoASy may function as a pro cell survival protein, either by coordinating cell signalling or through Coenzyme A-mediated antiapoptotic processes.
|Title:||Investigating the regulation and cellular functions of CoA Synthase|
|Additional information:||Permission for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Structural and Molecular Biology|
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