Research objectives and content
Biochemical control can now be quantified, but there are no studies that quantify and explain the regulation of the citric acid cycle. Metabolic control analysis will be used to provide a full system-level description of the regulation of the cycle and associated respiration in mitochondria. Changes in the rates of reactions and the concentrations of intermediates following specific small changes will be monitored, and control analysis will be applied to quantify regulation. We will measure the partial response coefficients that quantify the relative different regulatory routes through the internal effectors and the regulation by external effectors such as calcium. This description will then be used as a framework for the integration, interpretation and understanding of the wealth of mechanistic detail already available. The results will provide quantitative answers to many questions of the sort: "How much will the citric acid cycle change rate if we change the activity of each cycle enzyme?" and "When energy demand increases, how strongly do different metabolic routes cause the cycle to accelerate?".
Training content (objective, benefit and expected impact)
This project will project a full training in the application of modern metabolic control analysis to mitochondrial function. A control and regulation analysis of the citric acid cycle with provide a platform for a proper understanding of its regulation.
Links with industry / industrial relevance (22)
Control analysis is likely to underpin biotechnological advances in the future, and this project will act as an example of how regulation in central pathways can be measured, understood, and subsequently manipulated.