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<p>Phase separation of biomolecules regulates a wide variety of intracellular functions. This process generates membraneless compartments called biomolecular condensates, which can enrich or exclude macromolecules. This property has been exploited to control metabolic pathways by selectively sequestering enzymes within condensates. Here we analyze the conditions under which biomolecular condensates can amplify the yield or selectivity of diverse metabolic pathways. For all these pathways, we show that the efficacy of phase separation can be approximately predicted by a single metric comprising two coarse-grained parameters: the fraction of the enzyme partitioning into the condensates and the change in the enzyme activity inside compared with outside the condensates. We validated the metric using genetically encoded engineered—synthetic—condensates in yeast to regulate acetoin biosynthesis. This metric can guide future experimental efforts in quantifying the relevant parameters to optimize metabolic flux in engineered condensates.</p><p></p>

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Principles of metabolic pathway control by biomolecular condensates in cells

  • 期刊论文

  • 发表日期：

    2025年3月12日

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  • Dongheon Lee,
  • Mackenzie T. Walls,
  • Ka-Hei Siu,
  • Yifan Dai,
  • Ke Xu,
  • Clifford P. Brangwynne,
  • Ashutosh Chilkoti,
  • José L. Avalos,
  • Lingchong You

摘要

Phase separation of biomolecules regulates a wide variety of intracellular functions. This process generates membraneless compartments called biomolecular condensates, which can enrich or exclude macromolecules. This property has been exploited to control metabolic pathways by selectively sequestering enzymes within condensates. Here we analyze the conditions under which biomolecular condensates can amplify the yield or selectivity of diverse metabolic pathways. For all these pathways, we show that the efficacy of phase separation can be approximately predicted by a single metric comprising two coarse-grained parameters: the fraction of the enzyme partitioning into the condensates and the change in the enzyme activity inside compared with outside the condensates. We validated the metric using genetically encoded engineered—synthetic—condensates in yeast to regulate acetoin biosynthesis. This metric can guide future experimental efforts in quantifying the relevant parameters to optimize metabolic flux in engineered condensates.