Yu, Bess Yi Kun; (2024) Elucidating the molecular mechanisms of the antioxidant function of CoA and protein CoAlation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The role of coenzyme A (CoA) in cellular metabolism had long been established but its role as an antioxidant is emerging in recent years. Using mass spectrometry analysis, more than 2100 proteins from mammalian and bacterial cells were found to be modified by CoA through disulfide bond with protein cysteine thiol groups during oxidative or metabolic stress. The tumour suppressor, P53 and the metastasis suppressor, NME1 were found to be modified by CoA in diamide-treated mammalian cells. Here, we investigated the role of the metabolic integrator CoA in regulating the function of p53, KRAS (a protooncogene encoded protein) and NME1. Our findings show that p53 and KRAS are modified in vitro but in vivo studies proved difficult. NME1 was CoAlated in vitro and in oxidative and metabolically stressed cells. Furthermore, the NDPK activity of NME1 is inhibited by CoA through covalent and non-covalent modifications. In tandem with this, we searched for candidates of a key player of the CoAlation/deCoAlation cycle, CoA disulfide reductase (CoADR), by fishing for CoA-binding partners from mammalian cells and tissues using affinity chromatography techniques. With structural analyses, AIFM1 was identified to be a potential CoADR candidate. Our findings show that it possesses basal CoADR activity.

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