The Pyrimidine Synthesis Modulon: A Stabilised Oscillatory Network Governed by Interferon Signalling. — ASN Events
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  3. The Pyrimidine Synthesis Modulon: A Stabilised Oscillatory Network Governed by Interferon Signalling.

The Pyrimidine Synthesis Modulon: A Stabilised Oscillatory Network Governed by Interferon Signalling. (#316)

Andrew Peel 1 , Tim Shaw 2
  1. The University of Melbourne, Parkville, VIC, Australia
  2. Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia

Background

Living cells simultaneously perform multitudes of precise, stringently regulated functions to co-ordinate interactions of the ~30,000 node gene-protein and protein-protein networks encoded by the genome, a feat achieved with remarkable efficiency (<8 pW per cell), using imprecise functional units with a large amount of internal redundancy and feedback. At all levels, noisy, overlapping and often contradictory input signals are integrated and processed to produce stable regulated outputs. Recognition of this striking resemblance to computing networks has inspired the exploration of a new and expanding area of biological electronics, which aims to use electrical engineering concepts to emulate complex biological processes.

Defining characteristics of complex biological networks, which have resulted from millions of years of evolutionary experiment, are self-organization, robustness and plasticity. They are stable to fluctuations (noise) in “expected” input, but prone to failure when challenged by unusually large or prolonged “unexpected” input, to which their response is a self-organized transition to a new meta-stable state, or failing to achieve that, to extinction. The transition phase is typically scale-free and describable by simple power laws of the form y = axb. The network becomes refractory to further input and ultimately fails or shuts down if it lacks a required input, or if the amplitude or frequency of an input signal exceeds a critical threshold.

Modeling and Results

We devised an electronic analogue of the evolutionarily ancient biochemical pathway for de novo pyrimidine synthesis, which requires six enzymatic reactions, the fourth being coupled to mitochondrial respiration. Rate-limiting steps are directly or indirectly governed by interferon signaling which regulates flux through the pathway via control of gene expression and gene product stability. The model predicts that intermittent pulses of interferon stimulation are required to de-repress the pathway and that over-stimulation will cause mitochondrial “burn-out”, consistent with many published observations.