A perspective on the discovery of enzyme activators

The evolution of small molecule enzyme activators

“…Secondly, as activators increase the reaction rate, the reaction curve changes; thus, the portion of the reaction curve where steady-state kinetics can be applied is smaller. 9 Therefore, this shortens the window for measuring initial rate and steady states which in turn decreases reliability. The mechanism of action is also important for understanding and identifying activators as they may bind or interact with the enzyme before or after substrate binding.…”

“…Activators that decrease K m are referred to as K-type and those that increased V max as V-type activators and therefore both of these parameters must be assessed to characterize activators. 9,22 Traditional methods for identifying inhibitors can also be employed for the identification of enzyme activators. Fluorescence resonance energy transfer (FRET) and other fluorescent based assay, activity-based protein profiling (ABPP) are some of the methods that have proved successful in the literature.…”

“…Firstly, there is a lack of tool compounds that can be used for the development of enzyme activation assays. 9,19,20 This is not always an issue for identifying inhibitors, as there are alternate ways to identify an expected decrease in reaction rate when the enzyme is fully inhibited. Secondly, as activators increase the reaction rate, the reaction curve changes; thus, the portion of the reaction curve where steadystate kinetics can be applied is smaller.…”

“…Many prior reports focus on kinase activation, 9–12 inhibition, 13–16 or a small cohort of kinase and non-kinase activators. 17 This review aims to highlight the potential and progress of small molecule non-kinase enzyme activators.…”

“…8 In non-essential activation the catalytic reaction can occur with and without the presence of the activator molecule, often increasing activity beyond existing basal level however, with essential activation, the catalytic reaction will not occur without the activator. 8,9 Essential activation occurs physiologically for some enzymes with cofactors, substrates and metal ions acting as an endogenous activator. Thus, small molecule activators can act through replacement of essential physiological molecules required for enzyme activity or by alternate mechanisms and sites on the enzyme surface.…”