Single-molecule theory of enzymatic inhibition

Tal Robin, Shlomi Reuveni () and Michael Urbakh
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Tal Robin: Tel Aviv University
Shlomi Reuveni: Tel Aviv University
Michael Urbakh: Tel Aviv University

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02995-6

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