BBSRC BB/F019602/1, "Post-transcriptional feedback control of polyamine metabolism in yeast: an integrated modelling and experimental investigation",

PI's Professor Declan Bates (University of Exeter), Dr. I. Stansfield and Dr Heather Wallace, (University of Aberdeen)

A new complete predictive model of the polyamine metabolism in the yeast Saccharomyces cerevisiae is developed using a Systems Biology approach incorporating enzyme kinetics, statistical analysis, control engineering and experimental molecular biology of translation.

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, coenzyme A synthesis and components of polyamine pathway are potential targets for cancer therapeutics. Unregulated polyamine synthesis can trigger uncontrolled cell proliferation. Conversely, polyamine depletion can cause apoptosis, and during development, defects leading to mental retardation in humans.

Our approach uncovers the multiple feedback control mechanisms in the polyamine metabolic pathway; also it provides source of robustness and its associated dynamical properties. The main focus is highly conserved negative feedback loop regulating level of enzyme Spe1, the enzyme catalysing the first step in the polyamine biosynthesis pathway by the protein Antizyme synthesized by a polyamine-dependent translational frameshifting mechanism.

The non-linear dynamical model is based on data obtained from specially designed experiments on translational frameshifting and readthrough. The experimental data are analyzed and incorporated via statistical functions in corresponding Antizyme synthesis and Antizyme/Spe1 degradation modules of the model. Also model structure includes polyamine biosynthesis pathway module based on kinetics data for 6 enzymes and adapted for use with two other modules.

This quantitative model of the polyamine "controller" reproduces experimental data and predicts polyamine content under normal conditions and at various decease-induced scenarios that cannot be seen from experiments.

Possible applications: pharmacology; toxicology, preclinical drug development for cancer and neurodegenerative disorders: anti-cancer drug DFMO, Snyder-Robinson Syndrome.

Key references

  • C. Rodriguez-Caso, R. Montanez, M. Cascante, F. Sanchez-Jimenes, and M. A. Medina, Mathematical Modeling of Polyamine Metabolism in Mammals, The journal of biological chemistry , 281, 31, 21799-21812, (2006).

  • M. Gilchrista, A. Wagner, A model of protein translation including codon bias, nonsense errors, and ribosome recycling, Journal of Theoretical Biology, 239, 417-434, (2006).

  • Kim, J, Bates, DG, Postlethwaite, I Ma L, and Iglesias P, Robustness analysis of biochemical network models, IET Systems Biology, 152, 96-104, (2006).



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