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<p>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 a defined spatial organization of the metabolon clusters is imperative for substrate channeling. Grounded in both experiments and simulations, these findings provide a framework for understanding the organization and function of metabolons across diverse metabolic pathways.</p>

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Complete enzyme clustering enhances coenzyme Q biosynthesis via substrate channeling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月29日

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  • Dianzhuo Wang,
  • Andrea Gottinger,
  • Jio Jeong,
  • Callum R. Nicoll,
  • Junlang Liu,
  • Tereza Kadavá,
  • Domiziana Cecchini,
  • Marco Malatesta,
  • Albert J. R. Heck,
  • Andrea Mattevi,
  • Eugene I. Shakhnovich

摘要

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 a defined spatial organization of the metabolon clusters is imperative for substrate channeling. Grounded in both experiments and simulations, these findings provide a framework for understanding the organization and function of metabolons across diverse metabolic pathways.