Abstract
Natural biochemical systems are ubiquitously organized both in space and time. Engineering the spatial organization of biochemistry has emerged as a key theme of synthetic biology, with numerous technologies promising improved biosynthetic pathway performance. One strategy, however, may produce disparate results for different biosynthetic pathways. We use a spatially resolved kinetic model to explore this fundamental design choice in systems and synthetic biology. We predict that two example biosynthetic pathways have distinct optimal organization strategies that vary based on pathway-dependent and cell-extrinsic factors. Moreover, we demonstrate that the optimal design varies as a function of kinetic and biophysical properties, as well as culture conditions. Our results suggest that organizing biosynthesis has the potential to substantially improve performance, but that choosing the appropriate strategy is key. The flexible design-space analysis we propose can be adapted to diverse biosynthetic pathways, and lays a foundation to rationally choose organization strategies for biosynthesis.
Highlights
Natural biochemical systems are ubiquitously organized both in space and time
We will outline the potential metabolic engineering benefits that could be derived from pathway organization using two different strategies: encapsulation in the propanediol utilization (Pdu) microcompartment of Salmonella and other enteric bacteria, and organization using a scaffold (Fig. 1C)
We find that encapsulation of native Pdu metabolism in an organelle is practically as effective as large improvements in kcat, and more effective than large improvements in KM, with respect to increasing the total flux through the pathway (Fig. 2C)
Summary
Natural biochemical systems are ubiquitously organized both in space and time. Engineering the spatial organization of biochemistry has emerged as a key theme of synthetic biology, with numerous technologies promising improved biosynthetic pathway performance. A new wave of synthetic biology technologies aims to address these key issues using a diverse array of strategies, while preparing to deploy engineered microbes widely and safely These cutting-edge approaches include cell-free approaches to protein and small molecule synthesis[5,6,7,8,9,10,11], dynamic control of metabolite concentrations[12] and of transcription and translation at the RNA level[13,14], robust approaches to biocontainment[15], sensing of diverse small molecules[16], establishing consortia of synergistic microbes[17,18], and discovering enzymes facilitating previously unknown catalyses[19,20]. It is thought that they function both by protecting the cellular contents from toxic intermediates[42] and by increasing the local concentration of the kinetically relevant intermediate inside the organelle[43]
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