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bioRxiv · 10.1101/2025.05.24.655883

Complete Enzyme Clustering Enhances Coenzyme Q Biosynthesisvia Substrate Channeling

Wang, D.·Gottinger, A.·Jeong, J.·Nicoll, C. R.·Liu, J.·Kadav, T.·Cecchini, D.·Malatesta, M.·Heck, A. J. R.·Mattevi, A.·Shakhnovich, E.
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Abstract

Metabolons - transient assemblies of sequential metabolic enzymes - facilitate the reactions of multi-step metabolic pathways, yet, how they mechanistically bolster metabolic flux remains unknown. Here, we investigate the molecular determinants of metabolon formation in coenzyme Q (CoQ) biosynthesis using coarse-grained molecular dynamics simulations and biochemical experiments. We show that the COQ metabolon forms at the critical region of a phase transition, where both metabolon clustering and metabolic flux exhibit coordinated sigmoidal responses to changes in protein-protein interaction strength. These complete metabolons enable substrate channeling between sequential enzymes, leading to a crucial enhancement of CoQ production efficiency. Selectively disrupting protein-protein interactions and randomly shuffling the interaction network demonstrate that protein-proximity rather than fine structure of the metabolon clusters is imperative for substrate channeling. Grounded in both experiment and simulation, these findings provide a framework for understanding the organization and function of metabolons across diverse metabolic pathways.

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Wang, D., Gottinger, A., Jeong, J., Nicoll, C. R., Liu, J., Kadav, T., Cecchini, D., Malatesta, M., Heck, A. J. R., Mattevi, A., Shakhnovich, E.. 2025-05-28. Complete Enzyme Clustering Enhances Coenzyme Q Biosynthesisvia Substrate Channeling. https://doi.org/10.1101/2025.05.24.655883

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