PT - JOURNAL ARTICLE AU - Tal Rotbart AU - Shlomi Reuveni AU - Michael Urbakh TI - Single-enzyme approach predicts natural emergence of inhibitor-activator duality AID - 10.1101/095562 DP - 2016 Jan 01 TA - bioRxiv PG - 095562 4099 - http://biorxiv.org/content/early/2016/12/20/095562.short 4100 - http://biorxiv.org/content/early/2016/12/20/095562.full AB - The classical theory of enzymatic inhibition aims to quantitatively describe the effect of certain molecules—called inhibitors—on the progression of enzymatic reactions, but “non-classical effects” and “anomalies” which seem to fall beyond its scope have forced practitioners and others to repeatedly patch and mend it ad-hoc. For example, depending on concentrations, some molecules can either inhibit, or facilitate, the progression of an enzymatic reaction. This duality gives rise to non-monotonic dose response curves which seriously complicate high throughput inhibitor screens and drug development, but it is widely believed that the three canonical modes of inhibition—competitive, uncompetitive, and mixed—cannot account for it. To critically test this view, 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 cannot undermine the validity of classical results in the case of competitive inhibition; but that it should strongly change our view on the uncompetitive and mixed modes of inhibition. In particular, we show that inhibitor-activator duality is inherent to these modes of “inhibition”, and state—in terms of experimentally measurable quantities—a condition assuring its emergence. Fundamental and practical implications of our findings are discussed.