Enhancement of enzymatic activity by biomolecular condensates through pH buffering

F. Stoffel, M. Papp, M. Gil-Garcia, A. M. Küffner, A. I. Benítez-Mateos, R. P. B. Jacquat, N. Galvanetto, L. Faltova and P. Arosio ()
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F. Stoffel: ETH Zurich
M. Papp: ETH Zurich
M. Gil-Garcia: ETH Zurich
A. M. Küffner: ETH Zurich
A. I. Benítez-Mateos: ETH Zurich
R. P. B. Jacquat: ETH Zurich
N. Galvanetto: University of Zurich
L. Faltova: ETH Zurich
P. Arosio: ETH Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Biomolecular condensates can affect enzymatic reactions by locally changing not only concentrations of molecules but also their environment. Since protein conformations can differ between the dense and dilute phase, phase separation can particularly modulate enzymes characterized by a conformation-dependent activity. Here, we generate enzymatic condensates containing a lipase from Bacillus thermocatenulatus, which exhibits an equilibrium between a closed, inactive state, and an open, active conformation. We show that the activity of the enzyme increases inside the dense phase, leading to an enhancement of the overall reaction rate in the phase-separated system. Moreover, we demonstrate that these condensates can generate a more basic environment compared to the surrounding solution, maintaining a high enzymatic activity even in a solution pH interval that would be otherwise less favorable for the lipase. We further show that the formation of two phases with distinct pH values optimizes a cascade reaction involving two enzymes with different optimal pH conditions. Our results demonstrate that, through local pH buffering, biomolecular condensates can expand the optimal pH interval for enzymatic reactions and increase their robustness towards changes in environmental parameters. These findings have implications in biology and biotechnology for biocatalytic engineering, for instance for enabling network reactions with enzymes that require distinct pH values.

Date: 2025
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DOI: 10.1038/s41467-025-61013-8

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