Abstract
The polyamine molecules putrescine, spermidine and spermine are involved in a number of important cellular processes such as transcriptional silencing, translation, protection from reactive oxygen species and coenzyme A synthesis. Components of the polyamine pathway are also potential targets for cancer therapeutics, as unregulated polyamine synthesis can trigger uncontrolled cell proliferation. Conversely, polyamine depletion can cause apoptosis, and during development, defects leading to mental retardation in humans (Snyder-Robinson Syndrome). Controlling polyamine concentrations is thus a significant regulatory challenge for the cell, because there are multiple cellular requirements for polyamines as well as a need to homeostatically maintain their concentration within a certain non-toxic range. In the cell, polyamine concentrations are regulated by multiple mechanisms, the most important of which is a feedback control loop involving Spe1 (the enzyme catalysing the first step in the polyamine biosynthesis pathway) and the protein antizyme, which is synthesised via a +1 ribosomal frameshift during translation of the antizyme mRNA. In this talk I will present the first predictive model of the polyamine feedback controller, which has been developed and validated using a Systems Biology approach incorporating enzyme kinetics, control engineering and experimental molecular biology.