Enzymatic metabolons dramatically enhance metabolic fluxes of low- efficiency biochemical reactions

S Ranganathan and JL Liu and E Shakhnovich, BIOPHYSICAL JOURNAL, 122, 4555-4566 (2023).

DOI: 10.1016/j.bpj.2023.10.033

In this work, we investigate how spatial proximity of enzymes belonging to the same pathway (metabolon) affects metabolic flux. Using off- lattice Langevin dynamics 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 speedup for longer pathways and especially for reaction-limited enzymes, whereas, 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 nonspecific 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, whereas most diffusion-limited enzymes populate shorter pathways. Our findings point toward 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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