Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors

• DOI: 10.1016/j.csbj.2023.11.019
• Publication Date: 2023-11-14T21:25:05Z
• Authors: Alessandro Pesaresi
• Keywords: protein kinases; hormesis; exosite; Short Communication; proteases; enzyme activation; PTM enzymes

Activation-by-inhibition is a biochemical paradox seldom observed in exosite enzymes, wherein active site-bound inhibitors unexpectedly lead to enzyme activation. This intriguing phenomenon occurs at low, undersaturating substrate concentrations, posing significant challenge drug discovery, especially when targeting enzymes such as protein kinases, proteases, and other posttranslational modification enzymes. These often rely on accessory recognition sites known exosites, which contribute complex binding mechanisms unique kinetic behaviors. study aims provide theoretical explanation for nonallosteric mechanism-based activation-by-inhibition, shedding light the complexities of inhibiting solely through site targeting. Notably, dual activator-inhibitor behavior manifests nonmonotonic biphasic dose-response, emphasizing importance understanding role inhibitor concentration low levels. Our findings underscore potential widespread occurrence activation by inhibition, that may have been overlooked past, thus advocate novel strategies design consider impact exosites effectively target