Structural and functional studies of metabolic enzymes and their complexes

Thesis

Enzymes in Intermediate metabolism participate in highly complex protein-protein interactions to carry out their cellular functions. To gain insight into these complexes, an integrative structural biology approach is adopted. Here the novel human structures of aminolevulinate synthase 2 (hsALAS2), involved in haem biosynthesis, and the ATP specific succinyl-CoA synthetase complex (hsA-SCS), involved in the tricarboxylic acid cycle are solved. In both cases, the structures unveil novel enzymatic regulatory features important in the catalytic mechanism for the enzymes and provide insights into enzyme dysfunction in disease. The drugability of hsALAS2, for the treatment of haem related porphyria, is assessed with X-ray fragment screening campaigns and attempts are made to substantiate literature evidence of a quaternary complex between ALAS2 and A-SCS. In addition, the structures of protein complexes in the propionate catabolism pathway are pursued to understand conformational dynamics that underpin their respective reaction mechanisms. The data together builds our understanding of the complexity of protein-protein interactions and their proposed involvement in regulating metabolic flux and pathway cross talk.

Authors: Bailey, HJ

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English