Synthetic gene circuits for metabolic control: design trade-offs and constraints

A grand challenge in synthetic biology is to push the design of biomolecular circuits from purely genetic constructs towards systems that interface different levels of the cellular machinery, including signalling networks and metabolic pathways. In this paper, we focus on a genetic circuit for feedb...

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Bibliographic Details
Published in:Journal of the Royal Society interface 2013-01, Vol.10 (78), p.20120671-20120671
Main Authors: Oyarzún, Diego A., Stan, Guy-Bart V.
Format: Article
Language:English
Subjects:
Escherichia coli - genetics
Escherichia coli - metabolism
Feedback Control Design
Gene Regulatory Networks
Metabolic Control
Metabolic Engineering
Models, Genetic
Operon Regulation
Promoter Regions, Genetic
Ribosomes - genetics
Ribosomes - metabolism
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Summary:A grand challenge in synthetic biology is to push the design of biomolecular circuits from purely genetic constructs towards systems that interface different levels of the cellular machinery, including signalling networks and metabolic pathways. In this paper, we focus on a genetic circuit for feedback regulation of unbranched metabolic pathways. The objective of this feedback system is to dampen the effect of flux perturbations caused by changes in cellular demands or by engineered pathways consuming metabolic intermediates. We consider a mathematical model for a control circuit with an operon architecture, whereby the expression of all pathway enzymes is transcriptionally repressed by the metabolic product. We address the existence and stability of the steady state, the dynamic response of the network under perturbations, and their dependence on common tuneable knobs such as the promoter characteristic and ribosome binding site (RBS) strengths. Our analysis reveals trade-offs between the steady state of the enzymes and the intermediates, together with a separation principle between promoter and RBS design. We show that enzymatic saturation imposes limits on the parameter design space, which must be satisfied to prevent metabolite accumulation and guarantee the stability of the network. The use of promoters with a broad dynamic range and a small leaky expression enlarges the design space. Simulation results with realistic parameter values also suggest that the control circuit can effectively upregulate enzyme production to compensate flux perturbations.
ISSN:1742-5689
1742-5662
DOI:10.1098/rsif.2012.0671