Optimizing enzymatic catalysts for rapid turnover of substrates with low enzyme sequestration
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ORIGINAL ARTICLE
Optimizing enzymatic catalysts for rapid turnover of substrates with low enzyme sequestration Abhishek Deshpande1
· Thomas E. Ouldridge2
Received: 13 July 2020 / Accepted: 14 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Enzymes are central to both metabolism and information processing in cells. In both cases, an enzyme’s ability to accelerate a reaction without being consumed in the reaction is crucial. Nevertheless, enzymes are transiently sequestered when they bind to their substrates; this sequestration limits activity and potentially compromises information processing and signal transduction. In this article, we analyse the mechanism of enzyme–substrate catalysis from the perspective of minimizing the load on the enzymes through sequestration, while maintaining at least a minimum reaction flux. In particular, we ask: which binding free energies of the enzyme–substrate and enzyme–product reaction intermediates minimize the fraction of enzymes sequestered in complexes, while sustaining a certain minimal flux? Under reasonable biophysical assumptions, we find that the optimal design will saturate the bound on the minimal flux and reflects a basic trade-off in catalytic operation. If both binding free energies are too high, there is low sequestration, but the effective progress of the reaction is hampered. If both binding free energies are too low, there is high sequestration, and the reaction flux may also be suppressed in extreme cases. The optimal binding free energies are therefore neither too high nor too low, but in fact moderate. Moreover, the optimal difference in substrate and product binding free energies, which contributes to the thermodynamic driving force of the reaction, is in general strongly constrained by the intrinsic free-energy difference between products and reactants. Both the strategies of using a negative binding free-energy difference to drive the catalyst-bound reaction forward and of using a positive binding free-energy difference to enhance detachment of the product are limited in their efficacy.
1 Introduction Enzymatic catalysts are ubiquitous in biology, forming crucial parts of the networks that implement metabolism [1], signalling [2,3], and the central dogma of molecular biology [4]. Analysing the mechanism by which they function is fundamental to understanding the exquisite behaviour of Communicated by Michael Hinczewski. This paper is intended to be part of the special issue on Thermodynamics and Information Theory in Biology..
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Thomas E. Ouldridge [email protected] Abhishek Deshpande [email protected], [email protected]
1
Department of Mathematics, University of Wisconin Madison, Madison 53706, WI, United States of America
2
Imperial College Centre for Synthetic Biology and Department of Bioengineering, Imperial College London, London SW7 2AZ, UK
natural networks, to engineering existing systems [5,6], and to developing synthetic analogs de novo [7–9]. A catalytic enzyme enhances the overall rat
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