Single-molecule theory of enzymatic inhibition

Nature Communications
Tal RobinMichael Urbakh

Abstract

The classical theory of enzymatic inhibition takes a deterministic, bulk based approach to quantitatively describe how inhibitors affect the progression of enzymatic reactions. Catalysis at the single-enzyme level is, however, inherently stochastic which could lead to strong deviations from classical predictions. To explore this, we take the single-enzyme perspective and rebuild the theory of enzymatic inhibition from the bottom up. We find that accounting for multi-conformational enzyme structure and intrinsic randomness should strongly change our view on the uncompetitive and mixed modes of inhibition. There, stochastic fluctuations at the single-enzyme level could make inhibitors act as activators; and we state-in terms of experimentally measurable quantities-a mathematical condition for the emergence of this surprising phenomenon. Our findings could explain why certain molecules that inhibit enzymatic activity when substrate concentrations are high, elicit a non-monotonic dose response when substrate concentrations are low.

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Citations

Aug 1, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Richard G MorrisAlpha S Yap
Jun 24, 2020·The Journal of Chemical Physics·Somrita Ray, Shlomi Reuveni
Nov 23, 2019·Cells·Alveena AhmedGiuseppe Melacini
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Jun 20, 2019·Physical Review. E·Tal RobinMichael Urbakh
Jun 25, 2020·Physical Review. E·Anna S Bodrova, Igor M Sokolov
Apr 9, 2020·Frontiers in Cell and Developmental Biology·Yaron Ilan
Apr 20, 2019·Physical Review. E·Arnab Pal, V V Prasad
Sep 11, 2019·Physical Review. E·Anna S BodrovaIgor M Sokolov
Jan 3, 2021·International Journal of Biological Macromolecules·Amit DubeyAmaresh Kumar Sahoo
Jul 10, 2021·The Journal of Chemical Physics·Somrita Ray, Shlomi Reuveni
Jun 18, 2021·Computational and Structural Biotechnology Journal·Zahra Razaghi-MoghadamZoran Nikoloski
Oct 5, 2021·Chembiochem : a European Journal of Chemical Biology·Daisuke FujiwaraIkuo Fujii

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