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bioRxiv · 10.1101/2023.07.17.549414

Enzymatic metabolon improves kinetic efficiency of reaction-limited enzyme pathways

Ranganathan, S.·Liu, J.·Shakhnovich, E.
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Abstract

In this work we investigate how spatial proximity of enzymes belonging to the same pathway (metabolon) affects metabolic flux. Using off-lattice Langevin Dynamics (LD) simulations in tandem with a stochastic reaction-diffusion protocol and a semi-analytical reaction-diffusion model, we systematically explored how strength of protein-protein interactions, catalytic efficiency and protein-ligand interactions affect metabolic flux through the metabolon. Formation of a metabolon leads to a greater speed up for longer pathways and especially for reaction-limited enzymes while for fully optimized diffusion-limited enzymes the effect is negligible. Notably, specific cluster architectures are not a prerequisite for enhancing reaction flux. Simulations uncover the crucial role of optimal non-specific protein-ligand interactions in enhancing catalytic efficiency of a metabolon. Our theory implies and bioinformatics analysis confirms that longer catalytic pathways are enriched in less optimal enzymes while most diffusion-limited enzymes populate shorter pathways. Our findings point towards a plausible evolutionary strategy where enzymes compensate for less-than-optimal efficiency by increasing their local concentration in the clustered state.

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Ranganathan, S., Liu, J., Shakhnovich, E.. 2023-07-17. Enzymatic metabolon improves kinetic efficiency of reaction-limited enzyme pathways. https://doi.org/10.1101/2023.07.17.549414

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