Principles of metabolic pathway control by biomolecular condensates in cells

Abstract

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. Biomolecular condensates have emerged as a promising strategy to control metabolic reactions in living cells. Here the authors use mathematical modeling to uncover the key physical parameters that govern the outcomes of metabolic reactions modulated by condensates. These governing principles are then demonstrated experimentally by modulating the biosynthesis of metabolites in Saccharomyces cerevisiae.